Axl inhibitors for use in combination therapy for preventing, treating or managing metastatic cancer

ABSTRACT

This invention is directed to methods of preventing, treating or managing cancer, preferably metastatic cancer, in a patient. The methods comprise administering an effective amount of an Axl inhibitor in combination with the administration of an effective amount of one or more chemotherapeutic agents.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.15/077,648, filed Mar. 22, 2016 (now pending), which is a continuationof U.S. patent application Ser. No. 13/908,874, filed Jun. 3, 2013 (nowabandoned); which is a divisional of U.S. patent application Ser. No.12/688,746, filed Jan. 15, 2010 (now U.S. Pat. No. 8,546,433); whichclaims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional PatentApplication No. 61/145,448, filed Jan. 16, 2009. These applications areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

This invention is directed to combination therapies for the prevention,treatment, or management of metastatic cancer in a patient having canceror a patient having other proliferative diseases or disorders.

BACKGROUND OF THE INVENTION

All of the protein kinases that have been identified to date in thehuman genome share a highly conserved catalytic domain of around 300 aa.This domain folds into a bi-lobed structure in which resides ATP-bindingand catalytic sites. The complexity of protein kinase regulation allowsmany potential mechanisms of inhibition including competition withactivating ligands, modulation of positive and negative regulators,interference with protein dimerization, and allosteric or competitiveinhibition at the substrate or ATP binding sites.

Axl (also known as UFO, ARK, and Tyro7; nucleotide accession numbersNM_021913 and NM_001699; protein accession numbers NP_068713 andNP_001690) is a receptor protein tyrosine kinase (RTK) that comprises aC-terminal extracellular ligand-binding domain and N-terminalcytoplasmic region containing the catalytic domain. The extracellulardomain of Axl has a unique structure that juxtaposes immunoglobulin andfibronectin Type III repeats and is reminiscent of the structure ofneural cell adhesion molecules. Axl and its two close relatives, Mer/Nykand Sky (Tyro3/Rse/Dtk), collectively known as the Tyro3 family ofRTK's, all bind and are stimulated to varying degrees by the sameligand, Gas6 (growth arrest specific-6), a ˜76 kDa secreted protein withsignificant homology to the coagulation cascade regulator, Protein S. Inaddition to binding to ligands, the Axl extracellular domain has beenshown to undergo homophilic interactions that mediate cell aggregation,suggesting that one important function of Axl may be to mediatecell-cell adhesion.

Axl is predominantly expressed in the vasculature in both endothelialcells (EC's) and vascular smooth muscle cells (VSMC's) and in cells ofthe myeloid lineage and is also detected in breast epithelial cells,chondrocytes, Sertoli cells and neurons. Several functions includingprotection from apoptosis induced by serum starvation, TNF-α or theviral protein E1A, as well as migration and cell differentiation havebeen ascribed to Axl signaling in cell culture. However, Axl−/− miceexhibit no overt developmental phenotype and the physiological functionof Axl in vivo is not clearly established in the literature.

Angiogenesis (the formation of new blood vessels) is limited tofunctions such as wound healing and the female reproductive cycle inhealthy adults. This physiological process has been co-opted by tumors,thus securing an adequate blood supply that feeds tumor growth andfacilitates metastasis. Deregulated angiogenesis also a feature of manyother diseases (for example, psoriasis, rheumatoid arthritis,endometriosis and blindness due to age-related macular degeneration(AMD), retinopathy of prematurity and diabetes) and often contributes tothe progression or pathology of the condition.

The overexpression of Axl and/or its ligand has also been reported in awide variety of solid tumor types including, but not limited to, breast,renal, endometrial, ovarian, thyroid, non-small cell lung carcinoma, anduveal melanoma as well as in myeloid leukemia's. Furthermore, itpossesses transforming activity in NIH3T3 and 32D cells. It has beendemonstrated that loss of Axl expression in tumor cells blocks thegrowth of solid human neoplasms in an in vivo MDA-MB-231 breastcarcinoma xenograft model. Taken together, these data suggest Axlsignaling can independently regulate EC angiogenesis and tumor growthand thus represents a novel target class for tumor therapeuticdevelopment.

The expression of Axl and Gas6 proteins is upregulated in a variety ofother disease states including endometriosis, vascular injury and kidneydisease and Axl signaling is functionally implicated in the latter twoindications. Axl-Gas6 signaling amplifies platelet responses and isimplicated in thrombus formation. Axl may thus potentially represent atherapeutic target for a number of diverse pathological conditionsincluding solid tumors, including, but not limited to, breast, renal,endometrial, ovarian, thyroid, non-small cell lung carcinoma and uvealmelanoma; liquid tumors, including but not limited to, leukemias(particularly myeloid leukemias) and lymphomas; endometriosis, vasculardisease/injury (including but not limited to restenosis, atherosclerosisand thrombosis), psoriasis; visual impairment due to maculardegeneration; diabetic retinopathy and retinopathy of prematurity;kidney disease (including but not limited to glomerulonephritis,diabetic nephropathy and renal transplant rejection), rheumatoidarthritis; osteoporosis, osteoarthritis and cataracts.

U.S. Published Patent Application No. 20070213375, U.S. Published PatentApplication No. 20080153815, U.S. Published Patent Application No.20080188454, U.S. Published Patent Application No. 20080176847, U.S.Published Patent Application No. 20080188455, U.S. Published PatentApplication No. 20080182862, U.S. Published Patent Application No.20080188474, U.S. Published Patent Application No. 20080117789, U.S.Published Patent Application No. 20090111816, PCT Published PatentApplication No. WO 2007/0030680, PCT Published Patent Application No. WO2008/045978, PCT Published Patent Application No. WO 2008/083353, PCTPublished Patent Application No. WO 2008/0083357, PCT Published PatentApplication No. WO 2008/083367, PCT Published Patent Application No. WO2008/083354, PCT Published Patent Application No. WO 2008/083356, PCTPublished Patent Application No. WO 2008/080134, and PCT PublishedPatent Application No. WO 2009/054864, the disclosures of which areincorporated in full by reference herein in their entireties, disclosescompounds which are useful as Axl inhibitors.

SUMMARY OF THE INVENTION

This invention is directed to combination therapies that provide bettertherapeutic profiles than current single agent therapies or othercombination therapies utilizing Axl inhibitors. Encompassed by theinvention are combination therapies, of one or more AXL inhibitors withone or more chemotherapeutic agents, that have at least an additivepotency or at least an additive therapeutic effect. Preferably, theinvention is directed to combination therapies where the therapeuticefficacy is greater than additive, e.g., a synergy exists between an AXLinhibitor and one or more chemotherapeutic agents when co-administered.Preferably, such combination therapies also reduce or avoid unwanted oradverse effects. In certain embodiments, the combination therapies ofthe invention provide an improved overall therapy relative to theadministration of the therapeutic agents by themselves. In certainembodiments, doses of existing chemotherapeutic agents can be reduced oradministered less frequently in using the combination therapies of theinvention, thereby increasing patient compliance, improving therapy andreducing unwanted or adverse effects.

Accordingly, this invention is directed to combination therapiesdesigned to prevent, treat or manage cancer, preferably metastaticcancer, in a patient, wherein the combination therapies compriseadministering an Axl inhibitor to the patient in need thereof incombination with one or more chemotherapeutic agents. In particular,this invention provides methods of preventing, treating or managingcancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents.

In one embodiment, the Axl inhibitor utilized in the combinationtherapies of the invention is a compound of formula (I):

wherein:

-   R¹, R⁴ and R⁵ are each independently selected from the group    consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, —C(O)R⁸,    —C(O)N(R⁶)R⁷, and —C(═NR⁶)N(R⁶)R⁷;-   R² and R³ are each independently a polycyclic heteroaryl containing    more than 14 ring atoms optionally substituted by one or more    substituents selected from the group consisting of oxo, thioxo,    cyano, nitro, halo, haloalkyl, alkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heteroaryl, optionally substituted heterocyclyl,    —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—CN,    —R⁹—O—R—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R—S(O)_(p)R⁸ (where p    is 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H,    —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷,    —R⁹—N(R⁶)C(O)OR⁸, —R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1    or 2), —R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where p    is 0, 1 or 2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2);-   or R² is a polycyclic heteroaryl containing more than 14 ring atoms    as described above and R³ is selected from the group consisting of    aryl and heteroaryl, where the aryl and the heteroaryl are each    independently optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2);-   or R³ is a polycyclic heteroaryl containing more than 14 ring atoms    as described above, and R² is selected from the group consisting of    aryl and heteroaryl, where the aryl and the heteroaryl are each    independently optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2);-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted aralkenyl, optionally    substituted aralkynyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂, —R¹⁰—N(R⁸)₂,    —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷, together with    the common nitrogen to which they are both attached, form an    optionally substituted N-heteroaryl or an optionally substituted    N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl,    haloalkynyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    aralkynyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, and optionally substituted heteroarylalkynyl;-   each R⁹ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain, an optionally substituted straight or branched alkenylene    chain and an optionally substituted straight or branched alkynylene    chain;-   each R¹⁰ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain, an    optionally substituted straight or branched alkenylene chain and an    optionally substituted straight or branched alkynylene chain;-   each R¹¹ is independently selected from the group consisting of    hydrogen, alkyl, cyano, nitro and —OR⁸;-   each R¹² is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂, —R¹⁰—N(R⁸)₂,    —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or two R^(12's), together with the    common nitrogen to which they are both attached, form an optionally    substituted N-heterocyclyl or an optionally substituted    N-heteroaryl;-   each R¹³ is independently selected from the group consisting of a    direct bond, an optionally substituted straight or branched alkylene    chain and an optionally substituted straight or branched alkenylene    chain; and-   each R¹⁴ is independently selected from the group consisting of an    optionally substituted straight or branched alkylene chain and an    optionally substituted straight or branched alkenylene chain;-   as an isolated stereoisomer or mixture thereof or as a tautomer or    mixture thereof, or a pharmaceutically acceptable salt or N-oxide    thereof.

In another aspect, this invention provides in vivo assays to determinethe effectiveness of a compound of formula (I) in combination with oneor more chemotherapeutic agents in preventing, treating or managingcancer, preferably metastatic cancer, in a patient.

These and other aspects of the invention will be evident upon referenceto the following detailed description. To that end, certain patent andother documents are cited herein to more specifically set forth variousaspects of this invention. Each of these documents is herebyincorporated by reference in its entirety.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the effect of an Axl inhibitor (i.e., Compound A) on thenumber of macroscopic lung metastases in the mouse 4T1 breast tumormodel of metastatic cancer.

FIG. 2 shows the effect of an Axl inhibitor (i.e., Compound A) on thenumber of medium (≤2 mm) macroscopic lung metastases in the mouse 4T1breast tumor model of metastatic cancer.

FIG. 3 shows the effect of an Axl inhibitor (i.e., Compound A) on thenumber of large (>3 mm) macroscopic lung metastases in the mouse 4T1breast tumor model of metastatic cancer.

FIG. 4 shows the effect of an Axl inhibitor (i.e., Compound A) on thenumber of microscopic liver metastases in the mouse 4T1 breast tumormodel of metastatic cancer.

FIG. 5 shows the effect of an Axl inhibitor (i.e., Compound A) incombination with a chemotherapeutic agent (i.e., cisplatin) on thevolume of the primary tumor in the mouse 4T1 breast tumor model ofmetastatic cancer.

FIG. 6 shows the effect of an Axl inhibitor (i.e., Compound A) incombination with a chemotherapeutic agent (i.e., cisplatin) on thenumber of micrometastasis in the liver in the mouse 4T1 breast tumormodel of metastatic cancer.

FIG. 7 shows the effect of an Axl inhibitor (i.e., Compound A) incombination with a chemotherapeutic agent (i.e., cisplatin) on thenumber of large (>3 mm) metastases in the lung in the mouse 4T1 breasttumor model of metastatic cancer.

FIG. 8 shows the percentage of mice bearing large (>3 mm) metastasesafter treatment with an Axl inhibitor (i.e., Compound A) in combinationwith a chemotherapeutic agent (i.e., cisplatin) in the mouse 4T1 breasttumor model of metastatic cancer.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated:

“Amino” refers to the —NH₂ radical.

“Carboxy” refers to the —C(O)OH radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to twelve carbon atoms, preferably one toeight carbon atoms or one to six carbon atoms and which is attached tothe rest of the molecule by a single bond, for example, methyl, ethyl,n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, and the like.For purposes of this invention, the term “lower alkyl” refers to analkyl radical having one to six carbon atoms.

“Optionally substituted alkyl” refers to an alkyl radical, as definedabove, which is optionally substituted by one or more substituentsselected from the group consisting of halo, cyano, nitro, oxo, thioxo,trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰,—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)₂N(R²⁰)₂ where each R²⁰ is independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroarylalkyl, ortwo R²⁰'s, together with the common nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onedouble bond, having from two to twelve carbon atoms, preferably one toeight carbon atoms and which is attached to the rest of the molecule bya single bond, for example, ethenyl, prop-1-enyl, but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like.

“Optionally substituted alkenyl” refers to an alkenyl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of halo, cyano, nitro,oxo, thioxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰,—C(O)OR²⁰, —C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰,—N(R²⁰)S(O)₂R²⁰, —S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (wherep is 0, 1 or 2), and —S(O)₂N(R²⁰)₂ where each R²⁰ is independentlyselected from the group consisting of hydrogen, alkyl, haloalkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl, or two R²⁰'s, together with the commonnitrogen to which they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing at least onetriple bond, optionally containing at least one double bond, having fromtwo to twelve carbon atoms, preferably one to eight carbon atoms andwhich is attached to the rest of the molecule by a single bond, forexample, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

“Optionally substituted alkynyl” refers to an alkynyl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of halo, cyano, nitro,oxo, thioxo, trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰,—C(O)OR²⁰, —C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰,—N(R²⁰)S(O)₂R²⁰, —S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (wherep is 0, 1 or 2), and —S(O)₂N(R²⁰)₂ where each R²⁰ is independentlyselected from the group consisting of hydrogen, alkyl, haloalkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl and optionallysubstituted heteroarylalkyl, or two R²⁰'s, together with the commonnitrogen to which they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl.

“Straight or branched alkylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing nounsaturation and having from one to twelve carbon atoms, for example,methylene, ethylene, propylene, n-butylene, and the like. The alkylenechain is attached to the rest of the molecule through a single bond andto the radical group through a single bond. The points of attachment ofthe alkylene chain to the rest of the molecule and to the radical groupcan be through one carbon in the alkylene chain or through any twocarbons within the chain.

“Optionally substituted straight or branched alkylene chain” refers toan alkylene chain, as defined above, which is optionally substituted byone or more substituents selected from the group consisting of halo,cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo,trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰,—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)₂N(R²⁰)₂ where each R²⁰ is independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroarylalkyl, ortwo R²⁰'s, together with the common nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl.

“Straight or branched alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, for example,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a double bond or asingle bond and to the radical group through a double bond or a singlebond. The points of attachment of the alkenylene chain to the rest ofthe molecule and to the radical group can be through one carbon or anytwo carbons within the chain.

“Optionally substituted straight or branched alkenylene chain” refers toan alkenylene chain, as defined above, which is optionally substitutedby one or more substituents selected from the group consisting of halo,cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo,trimethylsilanyl, —OR²⁰, —OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰,—C(O)N(R²⁰)₂, —N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰,—S(O)_(t)OR²⁰ (where t is 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2),and —S(O)₂N(R²⁰)₂ where each R²⁰ is independently selected from thegroup consisting of hydrogen, alkyl, haloalkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heteroaryl and optionally substituted heteroarylalkyl, ortwo R²⁰'s, together with the common nitrogen to which they are bothattached, form an optionally substituted N-heterocyclyl or an optionallysubstituted N-heteroaryl.

“Straight or branched alkynylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onetriple bond and having from two to twelve carbon atoms, for example,propynylene, n-butynylene, and the like. The alkynylene chain isattached to the rest of the molecule through a single bond and to theradical group through a double bond or a single bond. The points ofattachment of the alkynylene chain to the rest of the molecule and tothe radical group can be through one carbon or any two carbons withinthe chain.

“Optionally substituted straight or branched alkynylene chain” refers toan alkynylene chain, as defined above, which is optionally substitutedby one or more substituents selected from the group consisting of alkyl,alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl,heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilanyl, —OR²⁰,—OC(O)—R²⁰, —N(R²⁰)₂, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,—N(R²⁰)C(O)OR²⁰, —N(R²⁰)C(O)R²⁰, —N(R²⁰)S(O)₂R²⁰, —S(O)_(t)OR²⁰ (where tis 1 or 2), —S(O)_(p)R²⁰ (where p is 0, 1 or 2), and —S(O)₂N(R²⁰)₂ whereeach R²⁰ is independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroarylalkyl, or two R²⁰'s,together with the common nitrogen to which they are both attached, forman optionally substituted N-heterocyclyl or an optionally substitutedN-heteroaryl.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 14 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical may be a monocyclic, bicyclic, ortricyclic system and which may include spiro ring systems. An arylradical is commonly, but not necessarily, attached to the parentmolecule via an aromatic ring of the aryl radical. For purposes of thisinvention, an “aryl” radical as defined herein can not contain ringshaving more than 7 members and cannot contain rings wherein twonon-adjacent ring atoms thereof are connected through an atom or a groupof atoms (i.e., a bridged ring system). Aryl radicals include, but arenot limited to, aryl radicals derived from acenaphthylene, anthracene,azulene, benzene, 6,7,8,9-tetrahydro-5H-benzo[7]annulene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene, andphenanthrene.

“Optionally substituted aryl” refers to an aryl radical, as definedabove, which is optionally substituted by one or more substituentsselected from the group consisting of alkyl, alkenyl, alkynyl, halo,haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰,—R²¹—C(O)N(R²⁰)₂, —R²¹—O—R²²—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰,—R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)₂R²⁰, —R²¹—C(═NR²⁰)N(R²⁰)₂,—R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1or 2), and —R²¹—S(O)₂N(R²⁰)₂, where each R²⁰ is independently selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroarylalkyl, or two R²⁰'s, together with the common nitrogen towhich they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl, each R²¹ isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R²² is a straight or branched alkylene oralkenylene chain.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(e) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike.

“Optionally substituted aralkyl” refers to an aralkyl radical, asdefined above, wherein the alkylene chain of the aralkyl radical is anoptionally substituted alkylene chain, as defined above, and each arylradical of the aralkyl radical is an optionally substituted arylradical, as defined above.

“Aralkenyl” refers to a radical of the formula —R_(d)—R_(c) where R_(d)is an alkenylene chain as defined above and R_(c) is one or more arylradicals as defined above.

“Optionally substituted aralkenyl” refers to an aralkenyl radical, asdefined above, wherein the alkenylene chain of the aralkenyl radical isan optionally substituted alkenylene chain, as defined above, and eacharyl radical of the aralkenyl radical is an optionally substituted arylradical, as defined above.

“Aralkynyl” refers to a radical of the formula —R_(e)R_(c) where R_(e)is an alkynylene chain as defined above and R_(c) is one or more arylradicals as defined above.

“Optionally substituted aralkynyl” refers to an aralkynyl radical, asdefined above, wherein the alkynylene chain of the aralkynyl radical isan optionally substituted alkynylene chain, as defined above, and eacharyl radical of the aralkynyl radical is an optionally substituted arylradical, as defined above.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused, spiro or bridged ring systems, having from threeto fifteen carbon atoms, preferably having from three to ten carbonatoms, more preferably from five to seven carbons and which is saturatedor unsaturated and attached to the rest of the molecule by a singlebond. For purposes of this invention, a bridged ring system is a systemwherein two non-adjacent ring atoms thereof are connected through anatom or a group of atoms, wherein the atom or the group of atoms are thebridging element. An example of a bridged cycloalkyl (monovalent)radical is norbornanyl (also called bicyclo[2.2.1]heptanyl). Forpurposes of this invention, a non-bridged ring system is a system whichdoes not contain a bridging element, as described above. For purposes ofthis invention, a fused ring system is a system wherein two adjacentring atoms thereof are connected through an atom or a group of atoms. Anexample of a fused cycloalkyl (monovalent) radical isdecahydronaphthalenyl (also called decalinyl). For purposes of thisinvention, a spiro ring system is a system wherein two rings are joinedvia a single carbon (quaternary) atom. An example of a spiro cycloalkyl(monovalent) radical is spiro[5.5]undecanyl. Monocyclic cycloalkylradicals do not include spiro, fused or bridged cycloalkyl radicals, butdo include for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals includefused, spiro or bridged cycloalkyl radicals, for example, C₁₀ radicalssuch as adamantanyl (bridged) and decalinyl (fused), and C₇ radicalssuch as bicyclo[3.2.0]heptanyl (fused), norbornanyl and norbomenyl(bridged), as well as substituted polycyclic radicals, for example,substituted C₇ radicals such as 7,7-dimethylbicyclo[2.2.1]heptanyl(bridged), and the like.

“Optionally substituted cycloalkyl” refers to a cycloalkyl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰,—R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰, —R²¹—N(R²⁰)C(O)R²⁰,—R²¹—N(R²⁰)S(O)₂R²⁰, —R²¹—C(═NR²⁰)N(R²⁰)₂, —R²¹—S(O)_(t)OR²⁰ (where t is1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1 or 2), and —R²¹—S(O)₂N(R²⁰)₂,where each R²⁰ is independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroarylalkyl, or two R²⁰'s,together with the common nitrogen to which they are both attached, forman optionally substituted N-heterocyclyl or an optionally substitutedN-heteroaryl, and each R²¹ is independently a direct bond or a straightor branched alkylene or alkenylene chain.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(g) whereR_(b) is an alkylene chain as defined above and R_(g) is a cycloalkylradical as defined above.

“Optionally substituted cycloalkylalkyl” refers to a cycloalkylalkylradical, as defined above, wherein the alkylene chain of thecycloalkylalkyl radical is an optionally substituted alkylene chain, asdefined above, and the cycloalkyl radical of the cycloalkylalkyl radicalis an optionally substituted cycloalkyl radical, as defined above.

“Cycloalkylalkenyl” refers to a radical of the formula —R_(d)R_(g) whereR_(d) is an alkenylene chain as defined above and R_(g) is a cycloalkylradical as defined above.

“Optionally substituted cycloalkylalkenyl” refers to a cycloalkylalkenylradical, as defined above, wherein the alkenylene chain of thecycloalkylalkenyl radical is an optionally substituted alkenylene chain,as defined above, and the cycloalkyl radical of the cycloalkylalkenylradical is an optionally substituted cycloalkyl radical as definedabove.

“Cycloalkylalkynyl” refers to a radical of the formula —R_(e)R_(g) whereR_(e) is an alkynylene radical as defined above and R_(g) is acycloalkyl radical as defined above.

“Optionally substituted cycloalkylalkynyl” refers to a cycloalkylalkynylradical, as defined above, wherein the alkynylene chain of thecycloalkylalkynyl radical is an optionally substituted alkynylene chain,as defined above, and the cycloalkyl radical of the cycloalkylalkynylradical is an optionally substituted cycloalkyl radical as definedabove.

“Halo” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, for example,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl,1-bromomethyl-2-bromoethyl, and the like.

“Haloalkenyl” refers to an alkenyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Haloalkynyl” refers to an alkynyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Heterocyclyl” refers to a stable 3- to 18-membered non-aromatic ringsystem radical which comprises one to twelve carbon atoms and from oneto six heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. Unless stated otherwise specifically in thespecification, the heterocyclyl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include spiro or bridgedring systems; and the nitrogen, carbon or sulfur atoms in theheterocyclyl radical may be optionally oxidized; the nitrogen atom maybe optionally quaternized; and the heterocyclyl radical may be partiallyor fully saturated. Examples of a bridged heterocyclyl include, but arenot limited to, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl,diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl,diazabicyclo[3.3.1]nonanyl, diazabicyclo[3.2.2]nonanyl andoxazabicyclo[2.2.1]heptanyl. A “bridged N-heterocyclyl” is a bridgedheterocyclyl containing at least one nitrogen, but which optionallycontains up to four additional heteroatoms selected from O, N and S. Forpurposes of this invention, a non-bridged ring system is a systemwherein no two non-adjacent ring atoms thereof are connected through anatom or a group of atoms. Examples of heterocyclyl radicals include, butare not limited to, dioxolanyl, 1,4-diazepanyl, decahydroisoquinolyl,imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl,octahydro-1H-pyrrolo[3,2-c]pyridinyl,octahydro-1H-pyrrolo[2,3-c]pyridinyl,octahydro-1H-pyrrolo[2,3-b]pyridinyl,octahydro-1H-pyrrolo[3,4-b]pyridinyl, octahydropyrrolo[3,4-c]pyrrolyl,octahydro-1H-pyrido[1,2-a]pyrazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, 3,7-diazabicyclo[3.3.1]nonan-3-yl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, thienyl[1,3]dithianyl,trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, azetidinyl,octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl,decahydroprazino[1,2-a]azepinyl, azepanyl, azabicyclo[3.2.1]octyl, and2,7-diazaspiro[4.4]nonanyl.

“Optionally substituted heterocyclyl” refers to a heterocyclyl radical,as defined above, which is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂,—R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰,—R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)₂R²⁰, —R²¹—C(═NR²⁰)N(R²⁰)₂,—R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1or 2), and —R²¹—S(O)₂N(R²⁰)₂, where each R²⁰ is independently selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroarylalkyl, or two R²⁰'s, together with the common nitrogen towhich they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹is independently a direct bond or a straight or branched alkylene oralkenylene chain.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe N-heterocyclyl radical to the rest of the molecule may be through anitrogen atom in the N-heterocyclyl radical or through a carbon in theN-heterocyclyl radical.

“Optionally substituted N-heterocyclyl” refers to an N-heterocyclyl, asdefined above, which is optionally substituted by one or moresubstituents as defined above for optionally substituted heterocyclyl.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(h) whereR_(b) is an alkylene chain as defined above and R_(h) is a heterocyclylradical as defined above, and when the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkylene chain at the nitrogen atom.

“Optionally substituted heterocyclylalkyl” refers to a heterocyclylalkylradical, as defined above, wherein the alkylene chain of theheterocyclylalkyl radical is an optionally substituted alkylene chain,as defined above, and the heterocyclyl radical of the heterocyclylalkylradical is an optionally substituted heterocyclyl radical, as definedabove.

“Heterocyclylalkenyl” refers to a radical of the formula —R_(d)R_(h)where R_(d) is an alkenylene chain as defined above and R_(h) is aheterocyclyl radical as defined above, and when the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkenylene chain at the nitrogen atom.

“Optionally substituted heterocyclylalkenyl” refers to aheterocyclylalkenyl radical, as defined above, wherein the alkenylenechain of the heterocyclylalkenyl radical is an optionally substitutedalkenylene chain, as defined above, and the heterocyclyl radical of theheterocyclylalkenyl radical is an optionally substituted heterocyclylradical, as defined above.

“Heterocyclylalkynyl” refers to a radical of the formula —R_(e)R_(h)where R_(e) is an alkynylene chain as defined above and R_(h) is aheterocyclyl radical as defined above, and when the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl may be attached tothe alkynylene chain at the nitrogen atom.

“Optionally substituted heterocyclylalkynyl” refers to aheterocyclylalkynyl radical, as defined above, wherein the alkynylenechain of the heterocyclylalkynyl radical is an optionally substitutedalkynylene chain, as defined above, and the heterocyclyl radical of theheterocyclylalkynyl radical is an optionally substituted heterocyclylradical, as defined above.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. A heteroaryl radical iscommonly, but not necessarily, attached to the parent molecule via anaromatic ring of the heteroaryl radical. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic or tricyclic ringsystem, which may include spiro or bridged ring systems; and thenitrogen, carbon or sulfur atoms in the heteroaryl radical may beoptionally oxidized and the nitrogen atom may be optionally quaternized.For purposes of this invention, the aromatic ring of the heteroarylradical need not contain a heteroatom, as long as one ring of theheteroaryl radical contains a heteroatom. For example benzo-fusedheterocyclyls such as 1,2,3,4-tetrahydroisoquinolin-7-yl are considereda “heteroaryl” for the purposes of this invention. Except for thepolycyclic heteroaryls containing more than 14 ring atoms, as definedbelow, a “heteroaryl” radical as defined herein can not contain ringshaving more than 7 members and cannot contain rings wherein twonon-adjacent members thereof are connected through an atom or a group ofatoms (i.e., a bridged ring system). Examples of heteroaryl radicalsinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,benzo[b][1,4]oxazinyl, benzo[b]azepinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl, 3,4-dihydro-2H-benzo[b][1,4]dioxepinyl,cyclopenta[4,5]thieno[2,3-d]pyrimidinyl such as6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 3,4-dihydro-2H-benzo[b][1,4]thiazinyl,5,6-dihydrobenzo[h]cinnolinyl,7′,8′-dihydro-5′H-spiro[[1,3]dioxolane-2,6′-quinoline]-3′-yl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinyl,3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazinyl,dihydropyridooxazinyl such as 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl,dihydropyridothiazinyl such as3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,furopyrimidinyl, furopyridazinyl, furopyrazinyl, isothiazolyl,imidazolyl, imidazopyrimidinyl, imidazopyridazinyl, imidazopyrazinyl,imidazo[1,2-a]pyridinyl, indazolyl, indolyl, indazolyl, isoindolyl,indolinyl, isoindolinyl, isoquinolinyl (isoquinolyl), indolizinyl,isoxazolyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl,2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,3′-oxo-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrido[3,2-b][1,4]oxazine]yl,7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, phenanthridinyl,pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl,pyridinyl (pyridyl), pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrazinyl, pyrimidinyl, pyridazinyl (pyridazyl), pyrrolyl,pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl,2H-pyrido[3,2-b][1,4]oxazinonyl, 1H-pyrido[2,3-b][1,4]oxazinonyl,pyrrolopyridinyl such as 1H-pyrrolo[2,3-b]pyridinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl, 2,3,4,5-tetrahydrobenzo[b]oxepinyl,6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridinyl,6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, 1,2,3,4-tetrahydroisoquinolin-7-yl, triazinyl,thieno[2,3-d]pyrimidinyl, thienopyrimidinyl (e.g.,thieno[3,2-d]pyrimidinyl), thieno[2,3-c]pyridinyl, thienopyridazinyl,thienopyrazinyl, and thiophenyl (thienyl).

“Optionally substituted heteroaryl” refers to a heteroaryl radical, asdefined above, which is optionally substituted by one or moresubstituents selected from the group consisting of alkyl, alkenyl,alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano,nitro, optionally substituted aryl, optionally substituted aralkyl,optionally substituted aralkenyl, optionally substituted aralkynyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionallysubstituted cycloalkylalkynyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰, —R²¹—N(R²⁰)₂,—R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂, —R²¹—N(R²⁰)C(O)OR²⁰,—R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)₂R²⁰2, —R²¹—C(═NR²⁰)N(R²⁰)₂,—R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰ (where p is 0, 1or 2), and —R²¹—S(O)₂N(R²⁰)₂, where each R²⁰ is independently selectedfrom the group consisting of hydrogen, alkyl, haloalkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heteroaryl and optionally substitutedheteroarylalkyl, or two R²⁰'s, together with the common nitrogen towhich they are both attached, form an optionally substitutedN-heterocyclyl or an optionally substituted N-heteroaryl, and each R²¹is independently a direct bond or a straight or branched alkylene oralkenylene chain.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe N-heteroaryl radical to the rest of the molecule may be through anitrogen atom in the N-heteroaryl radical or through a carbon atom inthe N-heteroaryl radical.

“Optionally substituted N-heteroaryl” refers to an N-heteroaryl, asdefined above, which is optionally substituted by one or moresubstituents as defined above for optionally substituted heteroaryl.

“Polycyclic heteroaryl containing more than 14 ring atoms” refers to a15- to 20-membered ring system radical comprising hydrogen atoms, one tofourteen carbon atoms, one to eight heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur, and at least one aromaticring. A “polycyclic heteroaryl containing more than 14 ring atoms”radical is commonly, but not necessarily, attached to the parentmolecule via an aromatic ring of the “polycyclic heteroaryl containingmore than 14 ring atoms” radical. For purposes of this invention, the“polycyclic heteroaryl containing more than 14 ring atoms” radical maybe a bicyclic, tricyclic or tetracyclic ring system, which may includefused or spiro ring systems; and the nitrogen, carbon or sulfur atoms inthe “polycyclic heteroaryl containing more than 14 ring atoms” radicalmay be optionally oxidized and the nitrogen atom may also be optionallyquaternized. For purposes of this invention, the aromatic ring of the“polycyclic heteroaryl containing more than 14 ring atoms” radical neednot contain a heteroatom, as long as one ring of the “polycyclicheteroaryl containing more than 14 ring atoms” radical contains aheteroatom. Examples of “polycyclic heteroaryl containing more than 14ring atoms” radicals include, but are not limited to,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,(Z)-dibenzo[b,f][1,4]thiazepin-11-yl,6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yland 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl.

“Optionally substituted polycyclic heteroaryl containing more than 14ring atoms” is meant to include “polycyclic heteroaryl containing morethan 14 ring atoms” radicals, as defined above, which are optionallysubstituted by one or more substituents selected from the groupconsisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,optionally substituted aralkyl, optionally substituted aralkenyl,optionally substituted aralkynyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substitutedcycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionallysubstituted heterocyclyl, optionally substituted heterocyclylalkyl,optionally substituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,optionally substituted heteroarylalkynyl, —R²¹—OR²⁰, —R²¹—OC(O)—R²⁰,—R²¹—N(R²⁰)₂, —R²¹—C(O)R²⁰, —R²¹—C(O)OR²⁰, —R²¹—C(O)N(R²⁰)₂,—R²¹—N(R²⁰)C(O)OR²⁰, —R²¹—N(R²⁰)C(O)R²⁰, —R²¹—N(R²⁰)S(O)_(t)R²⁰ (where tis 1 or 2), —R²¹—S(O)_(t)OR²⁰ (where t is 1 or 2), —R²¹—S(O)_(p)R²⁰(where p is 0, 1 or 2), and —R²¹—S(O)_(t)N(R²⁰)₂ (where t is 1 or 2),where each R²⁰ is independently selected from the group consisting ofhydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl,optionally substituted cycloalkylalkyl, optionally substituted aryl,optionally substituted aralkyl, optionally substituted heterocyclyl,optionally substituted heterocyclylalkyl, optionally substitutedheteroaryl and optionally substituted heteroarylalkyl, or two R²⁰'s,together with the common nitrogen to which they are both attached, mayoptionally form an optionally substituted N-heterocyclyl or anoptionally substituted N-heteroaryl, and each R²¹ is independently adirect bond or a straight or branched alkylene or alkenylene chain.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(i) whereR_(b) is an alkylene chain as defined above and R_(i) is a heteroarylradical as defined above, and when the heteroaryl is anitrogen-containing heteroaryl, the heteroaryl may be attached to thealkylene chain at the nitrogen atom.

“Optionally substituted heteroarylalkyl” refers to a heteroarylalkylradical, as defined above, wherein the alkylene chain of theheteroarylalkyl radical is an optionally substituted alkylene chain, asdefined above, and the heteroaryl radical of the heteroarylalkyl radicalis an optionally substituted heteroaryl radical, as defined above.

“Heteroarylalkenyl” refers to a radical of the formula —R_(d)R_(i) whereR_(d) is an alkenylene chain as defined above and R_(i) is a heteroarylradical as defined above, and when the heteroaryl is anitrogen-containing heteroaryl, the heteroaryl may be attached to thealkenylene chain at the nitrogen atom.

“Optionally substituted heteroarylalkenyl” refers to a heteroarylalkenylradical, as defined above, wherein the alkenylene chain of theheteroarylalkenyl radical is an optionally substituted alkenylene chain,as defined above, and the heteroaryl radical of the heteroarylalkenylradical is an optionally substituted heteroaryl radical, as definedabove.

“Heteroarylalkynyl” refers to a radical of the formula —R_(e)R_(i) whereR_(e) is an alkynylene chain as defined above and R_(i) is a heteroarylradical as defined above, and when the heteroaryl is anitrogen-containing heteroaryl, the heteroaryl may be attached to thealkynylene chain at the nitrogen atom.

“Optionally substituted heteroarylalkynyl” refers to a heteroarylalkynylradical, as defined above, wherein the alkynylene chain of theheteroarylalkynyl radical is an optionally substituted alkynylene chain,as defined above, and the heteroaryl radical of the heteroarylalkynylradical is an optionally substituted heteroaryl radical, as definedabove.

“Hydroxyalkyl” refers to an alkyl radical as defined above which issubstituted by one or more hydroxy radicals (—OH).

Certain chemical groups named herein may be preceded by a shorthandnotation indicating the total number of carbon atoms that are to befound in the indicated chemical group. For example; C₇-C₁₂alkyldescribes an alkyl group, as defined below, having a total of 7 to 12carbon atoms, and C₄-C₁₂cycloalkylalkyl describes a cycloalkylalkylgroup, as defined below, having a total of 4 to 12 carbon atoms. Thetotal number of carbons in the shorthand notation does not includecarbons that may exist in substituents of the group described.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

“Patient” means a mammal who has been diagnosed as having cancer and/ormetastatic cancer, or who is predisposed to having metastatic cancer dueto having cancer.

“Mammal” means any vertebrate of the class Mammalia. Humans and domesticanimals, such as cats, dogs, swine, cattle, sheep, goats, horses,rabbits, and the like are a particular focus. Preferably, for purposesof this invention, the mammal is a primate (e.g., monkey, baboon,chimpanzee and human), and more preferably, the mammal is a human.

“Optional” or “optionally” means that the subsequently described eventor circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution. However, when a first functional group is described as“optionally substituted,” and in turn, substituents on the firstfunctional group are also “optionally substituted” and so forth, for thepurposes of this invention, such iterations for a radical to beoptionally substituted are limited to three. Thus, groups described assubstituents on the third iteration are not themselves optionallysubstituted. For example, if an R group herein is defined as being“optionally substituted aryl” (the first iteration) and the optionalsubstituents for the “optionally substituted aryl” include “optionallysubstituted heteroaryl” (the second iteration) and the optionalsubstituents for the “optionally substituted heteroaryl” include“optionally substituted cycloalkyl” (the third iteration), the optionalsubstituents on the cycloalkyl can not be optionally substituted.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, benethamine,benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine,triethanolamine, tromethamine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline and caffeine.

A “pharmaceutical composition” refers to a formulation of a compound offormula (I) or a formulation of a chemotherapeutic agent describedherein and a medium generally accepted in the art for the delivery ofthe biologically active compound to mammals, for example, humans. Such amedium includes all pharmaceutically acceptable carriers, diluents orexcipients therefor.

“Therapeutically effective amount” refers to that amount of thetherapeutic agent sufficient to destroy, modify, control or removemestastatic cancer tissue. A therapeutically effective amount may referto the amount of therapeutic agents sufficient to delay or minimize thespread of metastatic cancer. A therapeutically effective amount may alsorefer to the amount of the therapeutic agent that provides a therapeuticbenefit in the treatment or management of metastatic cancer. Further, atherapeutically effective amount with respect to an Axl inhibitor of thecombination therapies of the invention means that amount of an Axlinhibitor in combination with one or more chemotherapeutic agents thatprovides a therapeutic benefit in the treatment or management ofmetastatic cancer, including the amelioration of symptoms associatedwith metastatic cancer. Used in connection with an amount of an Axlinhibito, the term can encompass an amount that improves overalltherapy, reduces or avoids unwanted effects, or enhances the therapeuticefficacy of or synergizes with the one or more chemotherapeutic agentsutilized in the combination therapies of the invention.

“Prophylactically effective amount” refers to that amount of theprophylactic agent sufficient to result in the prevention of metastaticcancer. A prophylactically effective amount may refer to the amount ofprophylactic agent sufficient to prevent metastatic cancer in a patient,including, but not limited to, those patients who are predisposed tocancer or previously exposed to carcinogens. A prophylacticallyeffective amount may also refer to the amount of the prophylactic agentthat provides a prophylactic benefit in the prevention of metastaticcancer. Further, a prophylactically effective amount with respect towith respect to an Axl inhibitor of the combination therapies of theinvention means that amount of an Axl inhibitor in combination withother chemotherapeutic agents, that provides a prophylactic benefit inthe prevention of metastatic cancer. Used in connection with an amountof an Axl inhibitor, the term can encompass an amount that improvesoverall prophylaxis or enhances the prophylactic efficacy of orsynergizes with another prophylactic or therapeutic agent.

As used herein, the terms “manage”, “managing” and “management” refer tothe beneficial effects that a patient derives from a combination therapyof the invention, which does not result in a cure of the metastaticcancer. In certain embodiments, a combination therapy of the invention“manages” metastatic cancer so as to prevent the progression orworsening of the metastatic cancer.

As used herein, the terms “prevent”, “preventing” and “prevention” referto the prevention of the spread or onset of metastatic cancer in apatient.

As used herein, the terms “treat”, “treating” and “treatment” refer tothe eradication, removal, modification or control of metastatic cancerthat results from the combination therapy of the invention. In certainembodiments, such terms refer to the minimizing or delay of the spreadof metastatic cancer.

The compounds of formula (I), or their pharmaceutically acceptablesalts, may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that maybe defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)-for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, such as HPLC using a chiralcolumn. When the compounds described herein contain olefinic doublebonds or other centers of geometric asymmetry, and unless specifiedotherwise, it is intended that the compounds include both E and Zgeometric isomers. Likewise, all tautomeric forms are also intended tobe included.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

“Atropisomers” are stereoisomers resulting from hindered rotation aboutsingle bonds where the barrier to rotation is high enough to allow forthe isolation of the conformers (Eliel, E. L.; Wilen, S. H.Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1994;Chapter 14). Atropisomerism is significant because it introduces anelement of chirality in the absence of stereogenic atoms. The inventionis meant to encompass atropisomers, for example in cases of limitedrotation around the single bonds emanating from the core triazolestructure, atropisomers are also possible and are also specificallyincluded in the compounds of the invention.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system wherein thecompounds of formula (I) are named herein as derivatives of the centralcore structure, i.e., the triazole structure. For complex chemical namesemployed herein, a substituent group is named before the group to whichit attaches. For example, cyclopropylethyl comprises an ethyl backbonewith cyclopropyl substituent. In chemical structure diagrams, all bondsare identified, except for some carbon atoms, which are assumed to bebonded to sufficient hydrogen atoms to complete the valency.

For purposes of this invention, the depiction of the bond attaching theR³ substituent to the parent triazole moiety in formula (I), as shownbelow:

is intended to include only the two regioisomers shown below, i.e.,compounds of formula (Ia) and (Ib):

The numbering system of the ring atoms in compounds of formula (Ia) isshown below:

For example, a compound of formula (Ia) wherein R¹, R⁴ and R⁵ are eachhydrogen, R² is 4-(2-(pyrrolidin-1-yl)ethoxy)phenyl and R³ is6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl; i.e., acompound of the following formula:

is named herein as1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.

The numbering system of the ring atoms in compounds of formula (Ib) isshown below:

Compounds of formula (Ib) are similarly named herein.

Embodiments of the Invention

Of the various aspects of the invention, as set forth herein, certainembodiments are preferred.

In one embodiment of the methods of preventing, treating or managingcancer in a patient comprising administering to the patient in needthereof a therapeutically or prophylactically effective amount of an Axlinhibitor in combination with the administration of a therapeutically orprophylactically effective amount of one or more chemotherapeuticagents, the Axl inhibitor is a compound of formula (I), as set forthabove in the Summary of the Invention, as an isolated stereoisomer ormixture thereof or as a tautomer or mixture thereof, or apharmaceutically acceptable salt or N-oxide thereof.

Of this embodiment, one preferred embodiment is wherein the compound offormula (I) is a compound of formula (Ia):

wherein R¹, R², R³, R⁴ and R⁵ are as described in the Summary of theInvention for compounds of formula (I), as an isolated stereoisomer ormixture thereof or as a tautomer or mixture thereof, or apharmaceutically acceptable salt or N-oxide thereof.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above, R² and R³ are each independently a polycyclicheteroaryl containing more than 14 ring atoms optionally substituted byone or more substituents selected from the group consisting of oxo,thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸,—R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—CN, —R⁹—O—R¹⁰—C(O)OR⁸,—R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R⁰—S(O)_(p)R⁸ (where p is 0, 1 or 2),—R⁹—O—R—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷,—R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹²,—R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2),—R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and R¹, R⁴, R⁵, eachR⁶, each R⁷, each R⁸, each R⁹, each R¹⁰, each R¹¹ and R¹² are asdescribed above for compounds of formula (Ia).

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R¹, R⁴ and R⁵ are each hydrogen;-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain; and-   each R¹¹ is independently selected from the group consisting of    hydrogen, alkyl, cyano, nitro and —OR⁸.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² and R³ are each independently a polycyclic heteroaryl containing    more than 14 ring atoms selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the method wherein the compound of formula (Ia) is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(5′,5′-dimethyl-6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above, R² is a polycyclic heteroaryl containing more than14 ring atoms optionally substituted by one or more substituentsselected from the group consisting of oxo, thioxo, cyano, nitro, halo,haloalkyl, alkyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted heteroaryl, optionallysubstituted heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸,—R⁹—O—R¹⁰—CN, —R⁹—O—R—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷,—R⁹—O—R¹⁰—S(O)_(p)R⁸ (where p is 0, 1 or 2), —R⁹—O—R—N(R⁶)R⁷,—R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,—R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,—R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is 1or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and —R⁹—S(O)_(t)N(R⁶)R⁷(where t is 1 or 2); R³ is selected from the group consisting of aryland heteroaryl, where the aryl and the heteroaryl are each independentlyoptionally substituted by one or more substitutents selected from thegroup consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂,—R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,—R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,—R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹² (where tis 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2), —R¹³—S(O)_(p)R¹²(where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2);and R¹, R⁴, R⁵, each R⁶, each R⁷, each R⁸, each R⁹, each R¹⁰, each R¹¹,each R¹², each R¹³ and each R¹⁴ are as described above for compounds offormula (Ia).

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R¹, R⁴ and R⁵ are each hydrogen;-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bondand an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain; each R¹¹ is independently selected from the group consisting    of hydrogen, alkyl, cyano, nitro and —OR⁸;-   each R¹² is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl, or two R^(12's), together with the common nitrogen    to which they are both attached, form an optionally substituted    N-heterocyclyl or an optionally substituted N-heteroaryl;-   each R¹³ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R¹, R⁴ and R⁵ are each hydrogen;-   R² is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2);-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain;-   each R¹² is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl, or two R^(12's), together with the common nitrogen    to which they are both attached, form an optionally substituted    N-heterocyclyl or an optionally substituted N-heteroaryl;-   each R¹³ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain.

Another embodiment is a method where, in the compound of formula (Ia) asset forth above:

-   R² is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and-   R³ is heteroaryl selected from the group consisting of pyridinyl,    pyrimidinyl, 4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl,    benzo[d]imidazolyl, 6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,    6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,    5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,    5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl,    2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,    3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,    3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl,    thieno[3,2-d]pyrimidinyl and    6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2).

Another embodiment is a method wherein the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   1-(6,7-dimethoxy-quinazolin-4-yl)-N³-(5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N³-(5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N³-(5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(2-chloro-7-methylthieno[3,2-d]pyrimidin-4-yl)-N³-(5′,5′-dimethyl-6,8,9,10-9tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above, R² is selected from the group consisting of aryl andheteroaryl, where the aryl and the heteroaryl are each independentlyoptionally substituted by one or more substitutents selected from thegroup consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂,—R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,—R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,—R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹² (where tis 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2), —R¹³—S(O)_(p)R¹²(where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2); R³is a polycyclic heteroaryl containing more than 14 ring atoms optionallysubstituted by one or more substituents selected from the groupconsisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, optionally substitutedheterocyclyl, —R⁹—OR⁸, —R⁹—O—R—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—CN,—R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R—S(O)_(p)R⁸ (where p is0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸,—R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷,—R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or2), —R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1or 2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and R¹, R⁴, R⁵, eachR⁶, each R⁷, each R⁸, each R⁹, each R¹⁰, each R¹¹, each R¹², each R¹³and each R¹⁴ are as described above for compounds of formula (I).

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain;-   each R¹¹ is independently selected from the group consisting of    hydrogen, alkyl, cyano, nitro and —OR⁸;-   each R¹² is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂, —R¹⁰—N(R⁸)₂,    —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or two R^(12's), together with the    common nitrogen to which they are both attached, form an optionally    substituted N-heterocyclyl or an optionally substituted    N-heteroaryl;-   each R¹³ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is aryl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹²,    —R¹³—C(O)N(R¹²)₂, —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³,    —R¹³—C(O)N(R¹²)—R¹⁴—OR¹², —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,    —R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where    t is 1 or 2), —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and    —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2).

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is aryl selected from the group consisting of phenyl and    6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹²,    —R¹³—C(O)N(R¹²)₂, —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³,    —R¹³—C(O)N(R¹²)—R¹⁴—OR¹², —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,    —R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where    t is 1 or 2), —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and    —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹²,    —R¹³—C(O)N(R¹²)₂, —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³,    —R¹³—C(O)N(R¹²)—R¹⁴—OR¹², —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,    —R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where    t is 1 or 2), —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and    —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2).

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, halo, haloalkyl, cyano,    and optionally substituted heterocyclyl where the optionally    substituted heterocyclyl is selected from the group consisting of    piperidinyl, piperazinyl, pyrrolidinyl, azepanyl,    decahydropyrazino[1,2-a]azepinyl, octahydropyrrolo[3,4-c]pyrrolyl,    azabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-b]pyrrolyl,    octahydropyrrolo[3,2-c]pyridinyl, 2,7-diazaspiro[4.4]nonanyl and    azetidinyl; each independently optionally substituted by one or two    substituents selected from the group consisting of —R⁹—OR⁸,    —R⁹—N(R⁶)R⁷, —R⁹—C(O)OR⁶, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)R⁷,    —R⁹—N(R⁶)C(O)OR⁷, alkyl, halo, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl;-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl and    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-3-yl, each    optionally substituted by one or more substituents selected from the    group consisting of alkyl, aryl, halo and —R⁹—OR⁸.

Another embodiment is the method where the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   N³-(4-(4-cyclohexanylpiperazin-1-yl)phenyl)-1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-methyl-3-phenylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-(4-(4-piperidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(indolin-2-on-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(morpholin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-cyclopentyl-2-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-(pyrrolidin-1-yl)piperidin-1-yl)-3-cyanophenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-(diethylamino)pyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(diethylamino)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-9-methoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperdin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-1-fluorobenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperdin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-1-fluorobenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(cyclohexyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-9-methoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(cyclohexyl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(4-methylpiperidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-dimethylaminopiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-chloro-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-trifluoromethyl-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-9,10-dimethoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-9,10,11-trimethoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(5-methyloctahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-pyrrolidin-1-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-pyrrolidin-1-yl-azepan-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-N-methylpiperidin-4-yl-piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N³-(3-fluoro-4-(4-(pyrrolidinyl)piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(5-propyloctahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(decahydropyrazino[1,2-a]azepin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(5-cyclopentyloctahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-(pyrrolidin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-yl-azepan-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(4-isopropylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(1-methyloctahydropyrrolo[3,4-b]pyrrol-5-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(N-methylcyclopentylamino)piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(dipropylamino)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(1-propyloctahydro-1H-pyrrolo[3,2-c]pyridine-5-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N³-(3-fluoro-4-(4-(N-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(tert-butyloxycarbonylamino)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-aminopiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(5-cyclohexyloctahydropyrrolo[3,4-c]pyrrolyl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(methylpiperidin-4-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-methyl-4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-cyclopentylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-N-methylpiperidin-4-ylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(N-isopropylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-pyrrolidin-1-ylazetidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-methyl-4-(4-(N-methylpiperazin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-((S)-3-(pyrrolidin-1-ylmethyl)pyrrolidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidinylmethyl)piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-((4aR,8aS)-decahydroisoquinolin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(octahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-(4-(3-pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(5-methyloctahydropyrrolo[3,4-c]pyrrolyl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(octahydropyrrolo[3,4-c]pyrrolyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-9-chloro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-9-chloro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(N-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-iodophenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl)-N³-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(3-(3R)-dimethylaminopyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N³-(3-methyl-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(4-phenyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl)-N³-(3-fluoro-4-(4-cyclohexylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(4-phenyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl)-N³-(4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(1-bicyclo[2.2.1]heptan-2-yl)-piperidin-4-ylphenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(1-cyclopropylmethylpiperidin-4-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-cyclopropylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(4-(1-bicyclo[2.2.1]heptan-2-yl)-piperidin-4-ylphenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(4-phenyl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine,    and-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of halo, alkyl,    heterocyclylalkenyl, —R¹³—OR¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹²,    —R¹³—C(O)N(R¹²)₂, and —R¹³—N(R¹²)C(O)R¹²;-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl and    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-3-yl, each    optionally substituted by one or more substituents selected from the    group consisting of alkyl, aryl, halo and —R⁹—OR⁸.

Another embodiment is the method where the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-(cyclopentyl)piperazin-1-ylcarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((2-pyrrolidin-1-ylethyl)aminocarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(2,2,6,6-tetramethylpiperidin-1-yl)ethoxyphenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((2-(dimethylamino)ethyl)aminocarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((2-(methoxy)ethyl)aminocarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((2-(pyrrolidin-1-yl)ethyl)aminocarbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((4-(pyrrolidin-1-yl)piperidin-1-yl)carbonyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-1-fluorobenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-9-methoxybenzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(2-(N-methylcyclopentylamino)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(N-methylpiperidin-4-yl-N-methylamino)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((N-butyl-N-acetoamino)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-(piperidin-1-yl)piperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(piperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(pyrrolidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(3-dimethylaminopyrrolidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(3-diethylaminopyrrolidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-pyrrolidin-1-ylpiperidin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-methylpiperazin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-isopropylpiperazin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(4-cyclopentylpiperazin-1-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(morpholin-4-ylprop-1-enyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(1-methylpiperidin-3-yl-oxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, halo, haloalkyl, cyano,    and optionally substituted heterocyclyl where the optionally    substituted heterocyclyl is selected from the group consisting of    piperidinyl, piperazinyl, pyrrolidinyl, azepanyl,    decahydropyrazino[1,2-a]azepinyl, octahydropyrrolo[3,4-c]pyrrolyl,    azabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-b]pyrrolyl,    octahydropyrrolo[3,2-c]pyridinyl, 2,7-diazaspiro[4.4]nonanyl and    azetidinyl; each independently optionally substituted by one or two    substituents selected from the group consisting of —R⁹—OR⁸,    —R⁹—N(R⁶)R⁷, —R⁹—C(O)OR⁶, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)R⁷,    —R⁹—N(R⁶)C(O)OR⁷, alkyl, halo, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl; and-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl and    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of alkyl, aryl, halo and —R⁹—OR⁸.

Another embodiment is the method where the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)-N³-(4-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)-N³-(3-fluoro-4-(4-(diethylamino)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N³-(4-(N-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N³-(3-fluoro-4-(4-cyclohexylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N³-(4-(4-(2S)-bicyclo[2.2.1]heptan-2-yl)-piperazinylphenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of halo, alkyl,    heterocyclylalkenyl, —R¹³—OR¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹²,    —R¹³—C(O)N(R¹²)₂, and —R¹³—N(R¹²)C(O)R¹²; and-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl and    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of alkyl, aryl, halo and —R⁹—OR⁸.

Another embodiment is the method where the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-N³-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)-N³-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, halo, haloalkyl, cyano,    and optionally substituted heterocyclyl where the optionally    substituted heterocyclyl is selected from the group consisting of    piperidinyl, piperazinyl, pyrrolidinyl, azepanyl,    decahydropyrazino[1,2-a]azepinyl, octahydropyrrolo[3,4-c]pyrrolyl,    azabicyclo[3.2.1]octyl, octahydropyrrolo[3,4-b]pyrrolyl,    octahydropyrrolo[3,2-c]pyridinyl, 2,7-diazaspiro[4.4]nonanyl and    azetidinyl; each independently optionally substituted by one or two    substituents selected from the group consisting of —R⁹—OR⁸,    —R⁹—N(R⁶)R⁷, —R⁹—C(O)OR⁶, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)R⁷,    —R⁹—N(R⁶)C(O)OR⁷, alkyl, halo, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl; and-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl, and    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl, each    optionally substituted by one or more substituents selected from the    group consisting of alkyl, aryl, halo and —R⁹—OR⁸.

Another embodiment is the method where the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-N³-(4-(N-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-cyclohexylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-((Z)-dibenzo[b,f][1,4]thiazepin-11-yl)-N³-(4-(4-N-methylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-((Z)-dibenzo[b,f][1,4]thiazepin-11-yl)-N³-(3-fluoro-4-(4-diethylaminopiperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N³-(4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidinylmethyl)piperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-((4aR,8aS)-decahydroisoquinolin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(octahydro-1H-pyrido[1,2-a]pyrazin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of halo, alkyl,    heterocyclylalkenyl, —R¹³—OR¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹²,    —R¹³—C(O)N(R¹²)₂, and —R¹³—N(R¹²)C(O)R¹²; and-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl, and    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the method where the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-((Z)-dibenzo[b,f][1,4]thiazepin-11-yl)-N³-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is phenyl optionally substituted by a substitutent selected from    the group consisting of optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl;-   R³ is selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl and    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2)-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain; and-   R¹² is independently selected from the group consisting of hydrogen,    alkyl, haloalkyl, alkenyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl and optionally substituted heteroarylalkyl.

Another embodiment is the method where the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((5-fluoroindolin-2-on-3-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((4-pyrrolidin-1-ylpiperidinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((4-cyclopentylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-((4-isopropylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(3-fluoro-4-(i    soindolin-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   R² is 6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹²,    —R¹³—C(O)N(R¹²)₂, —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³,    —R¹³—C(O)N(R¹²)—R¹⁴—OR¹², —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,    —R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where    t is 1 or 2), —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and    —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and each R⁶, each R⁷, each    R⁸, each R⁹, each R¹², each R¹³ and each R¹⁴ are as described above    for compounds of formula (Ia).

Another embodiment is the method where the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((bicyclo[2.2.1]heptan-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((bicyclo[2.2.1]heptan-2-yl)(methyl)amino)    6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-diethyl    amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-cyclopentylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(2-(S)-methyl    oxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(2-(S)-carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(8-diethyl    aminoethyl-9hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(3-(S)-fluoropyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(2-(S)-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(3-(R)-hydroxypyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(2-(R)-methylpyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(3-(S)-hydroxypyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(3-(R)-fluoropyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-cyclohexylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-cyclopropylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-methylpiperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(tetrahydrofuran-2-ylmethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-cyclobutylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(cyclopropylmethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(2-(diethyl    amino)ethyl)methylamino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-pyrrolidin-1-ylpiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(piperidin-1-ylmethyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(2-(dimethylamino)ethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(carb    oxymethyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7s)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethyl    amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((5-chiorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-carb    oxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   R² is heteroaryl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹²,    —R¹³—C(O)N(R¹²)₂, —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³,    —R¹³—C(O)N(R¹²)—R¹⁴—OR¹², —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,    —R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where    t is 1 or 2), —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and    —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2);-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸,    —R⁹—O—R¹⁰—CN, —R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷,    —R⁹—O—R—S(O)_(p)R⁸ (where p is 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷,    —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and each R⁶, each R⁷, each    R⁸, each R⁹, each R¹², each R¹³ and each R¹⁴ are as described above    for compounds of formula (Ia); and-   each R⁶, each R⁷, each R⁸, each R⁹, each R¹⁰, each R¹¹, each R¹²,    each R¹³ and each R¹⁴ are as described above for compounds of    formula (Ia).

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is heteroaryl selected from the group consisting of pyridinyl,    pyrimidinyl, 4,5-dihydro-1H-benzo[b]azepin-2 (3H)-on-8-yl,    benzo[d]imidazolyl, 6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,    6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,    5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,    5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl,    2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,    3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,    3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl, and    6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R² is selected from the group consisting of pyridinyl and    pyrimidinyl, each optionally substituted by one or more    substitutents selected from the group consisting of alkyl, alkenyl,    alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo,    cyano, nitro, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted aralkenyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted cycloalkylalkenyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(o)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2).

Another embodiment is the method where the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-(bicyclo[2.2.1]heptan-2-yl)piperazin-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-cyclopentyl-1,4-diazepan-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(6-aminopyridin-3-yl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-aminophenyl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-cyanophenyl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(benzo[d][1,3]dioxole-6-yl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-methyl    sulfonamidylphenyl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(2-diethyl    aminomethyl)pyrrolidin-1-ylpyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-diethyl    aminopyrrolidin-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-(4-(N-methylpiperazin-4-yl)piperidin-1-yl)-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-(pyrrolidin-1-yl)piperidin-1-yl)-5-methylpyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-piperidin-1-yl-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-(bicyclo[2.2.1]heptan-2-yl)-1,4-diazepan-1-yl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-(4-(pyrrolidin-1-yl)piperidin-1-yl)-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-piperidin-1-yl)-propanylpyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-(4-(piperidin-1-yl)piperidin-1-yl)-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(3-(4-dimethylaminopiperidin-1-yl)-(E)-propenyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(4-pyrrolidin-1-ylpiperidin-1-yl)pyrimidin-5-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(4-(piperidin-1-ylmethyl)piperidin-1-yl)pyrimidin-5-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-((4-piperidin-1-ylpiperidin-1-yl)carbonyl)pyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(4-cyclopropylmethylpiperazin-1-yl)pyridine-5-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(3-(S)-methyl-4-cyclopropylmethylpiperazin-1-yl)pyridine-5-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ia)as set forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   R² is selected from the group consisting of    4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl, benzo[d]imidazolyl,    6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,    6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,    5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,    5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl,    2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,    3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,    3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl, and    6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the method where the compound of formula (Ia), asset forth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(dimethylaminomethyl)-1H-benzo[d]imidazol-5-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-cyclopentyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-methyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(4-methylpiperazin-1-yl)carbonyl-5,6,7,8-tetrahydroquinolin-3-yl)-1H-1,2,4-triazole-3,5-diamine,    compound #31, 1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N³-(2-(pyrrolidin-1-ylmethyl)benzo[d]oxazol-5-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(4-(2-dimethylaminoethyl)-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl))-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl)-N³-(4-(2-dimethylaminoethyl)-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl))-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N³-(2-(1-(4-(2-(dimethylamino)ethyl)piperazin-1-yl)oxomethyl)benzo[b]thiophen-5-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-cyclopentyl-6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³    (2-cyclopentyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-(pyrrolidin-1-yl)-5,6,7,8-tetrahydroquinolin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(6-cyclopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((S)-7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(2-(cyclopropylmethyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where the compound of formula (Ia), asset forth above, is a compound of formula (Ia1):

wherein:

-   A is ═C(H)— or ═N—;-   each R^(2a) is independently selected from the group consisting of    —N(R^(12a))₂ and —N(R^(12a))C(O)R^(12a),-   or R^(2a) is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R²¹—C(O)OR²⁰,-   each R^(12a) is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl;-   R²⁰ is independently selected from the group consisting of hydrogen,    alkyl, alkenyl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl; and-   R²¹ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

Of the embodiment of utilizing a compound of formula (I), as set forthabove in the Summary of the Invention, in the methods of the invention,another embodiment is wherein the compound of formula (I) is a compoundof formula (Ib):

wherein R¹, R², R³, R⁴ and R⁵ are as described above in the Summary ofthe Invention for compounds of formula (I), as an isolated stereoisomeror mixture thereof or as a tautomer or mixture thereof, or apharmaceutically acceptable salt or N-oxide thereof.

Another embodiment is the method where, in the compound of formula (Ib)as set forth above, R² and R³ are each independently a polycyclicheteroaryl containing more than 14 ring atoms optionally substituted byone or more substituents selected from the group consisting of oxo,thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸,—R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—CN, —R⁹—O—R¹⁰—C(O)OR⁸,—R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R⁰—S(O)_(p)R⁸ (where p is 0, 1 or 2),—R⁹—O—R—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷,—R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹²,—R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2),—R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); and R¹, R⁴, R⁵, eachR⁶, each R⁷, each R⁸, each R⁹, each R¹⁰, each R¹¹ and R¹² are asdescribed above in the Summary of the Invention.

Another embodiment is the method where, in the compound of formula (Ib)as set forth above:

-   R¹, R⁴ and R⁵ are each hydrogen;-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, haloalkyl, optionally substituted aryl, optionally    substituted aralkyl, optionally substituted cycloalkyl, optionally    substituted cycloalkylalkyl, optionally substituted heterocyclyl,    optionally substituted heterocyclylalkyl, optionally substituted    heteroaryl, and optionally substituted heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain; and-   each R¹¹ is independently selected from the group consisting of    hydrogen, alkyl, cyano, nitro and —OR⁸.

Another embodiment is the method where, in the compound of formula (Ib)as set forth above:

-   R² and R³ are each independently a polycyclic heteroaryl containing    more than 14 ring atoms selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2)

Another embodiment is the method where the compound of formula (Ib), asset forth above, is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′[1,3]dioxolane]-3-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ib)as set forth above:

-   R² is selected from the group consisting of aryl and heteroaryl,    where the aryl and the heteroaryl are each independently optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸,    —R⁹—O—R¹⁰—CN, —R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷,    —R⁹—O—R¹⁰—S(O)_(p)R⁸ (where p is 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷,    —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the method where, in the compound of formula (Ib)as set forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   each R⁶ and R⁷ is independently selected from the group consisting    of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted heteroaryl,    optionally substituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R⁰—NO₂,    —R¹⁰—N(R⁸)₂, —R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷,    together with the common nitrogen to which they are both attached,    form an optionally substituted N-heteroaryl or an optionally    substituted N-heterocyclyl;-   each R⁸ is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, optionally substituted    aryl, optionally substituted aralkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl, and optionally substituted    heteroarylalkyl;-   each R⁹ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain;-   each R¹⁰ is an optionally substituted straight or branched alkylene    chain;-   each R¹¹ is independently selected from the group consisting of    hydrogen, alkyl, cyano, nitro and —OR⁸;-   each R¹² is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted    cycloalkyl, optionally substituted cycloalkylalkyl, optionally    substituted aryl, optionally substituted aralkyl, optionally    substituted heterocyclyl, optionally substituted heterocyclylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl, or two R^(12's), together with the common nitrogen    to which they are both attached, form an optionally substituted    N-heterocyclyl or an optionally substituted N-heteroaryl;-   each R¹³ is independently selected from the group consisting of a    direct bond and an optionally substituted straight or branched    alkylene chain; and-   each R¹⁴ is an optionally substituted straight or branched alkylene    chain.

Another embodiment is the method where, in the compound of formula (Ib)as set forth above:

-   R² is aryl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(o)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸,    —R⁹—O—R¹⁰—CN, —R⁹—O—R¹⁰—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷,    —R⁹—O—R¹⁰—S(O)_(p)R⁸ (where p is 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷,    —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2);

Another embodiment is the method where, in the compound of formula (Ib)as set forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   R² is aryl selected from the group consisting of phenyl and    6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted aralkynyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heterocyclylalkynyl, optionally substituted    heteroaryl, optionally substituted heteroarylalkyl, optionally    substituted heteroarylalkenyl, optionally substituted    heteroarylalkynyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the method where, in the compound of formula (Ib)as set forth above:

-   R² is phenyl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted cycloalkyl,    optionally substituted cycloalkylalkyl, optionally substituted    cycloalkylalkenyl, optionally substituted heterocyclyl, optionally    substituted heterocyclylalkyl, optionally substituted    heterocyclylalkenyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂,    —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(o)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2).

Another embodiment is the method where the compound of formula (Ib), asset forth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(3-fluoro-4-(4-(indolin-2-on-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(3-fluoro-4-(4-(morpholin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-(3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(7-methyl-6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl)-N⁵-(4-(N-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-((5-fluoroindolin-2-on-3-yl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-((4-pyrrolidin-1-ylpiperidinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-((4-cyclopentylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-((4-isopropylpiperazinyl)methyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(3-fluoro-4-(4-N-methylpiperid-4-ylpiperazinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(3-fluoro-4-(7-methyl-2,7-diazaspiro[4.4]nonan-2-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(3-fluoro-4-(3-pyrrolidin-1-ylazetidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(3-methyl-4-(4-(N-methylpiperazin-4-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl)-N⁵-(4-(4-pyrrolidin-1-ylpiperidinyl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(3-fluoro-(4-(3-pyrrolidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(3-fluoro-4-(4-cyclopropylmethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ib)as set forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   R² is 6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the method where the compound of formula (Ib), asset forth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-((bicyclo[2.2.1]heptan-2-yl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(S)-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where, in the compound of formula (Ib)as set forth above:

-   R¹, R⁴ and R⁵ are each independently hydrogen;-   R² is heteroaryl optionally substituted by one or more substitutents    selected from the group consisting of alkyl, alkenyl, alkynyl, halo,    haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro,    optionally substituted aryl, optionally substituted aralkyl,    optionally substituted aralkenyl, optionally substituted aralkynyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted cycloalkylalkynyl, optionally substituted    heterocyclyl, optionally substituted heterocyclylalkyl, optionally    substituted heterocyclylalkenyl, optionally substituted    heterocyclylalkynyl, optionally substituted heteroaryl, optionally    substituted heteroarylalkyl, optionally substituted    heteroarylalkenyl, optionally substituted heteroarylalkynyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(o)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸,    —R⁹—O—R¹⁰—CN, —R⁹—O—R—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷,    —R⁹—O—R¹⁰—S(O)_(p)R⁸ (where p is 0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷,    —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2);

Another embodiment is the method where, in the compound of formula (Ib)as set forth above:

-   R² is heteroaryl selected from the group consisting of pyridinyl,    pyrimidinyl, 4,5-dihydro-1H-benzo[b]azepin-2(3H)-on-8-yl,    benzo[d]imidazolyl, 6,7,8,9-tetrahydro-5H-pyrido[3,2-d]azepin-3-yl,    6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepin-3-yl,    5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl,    5,6,7,8-tetrahydroquinolin-3-yl, 1,2,3,4-tetrahydroisoquinolin-7-yl,    2,3,4,5-tetrahydrobenzo[b]oxepin-7-yl,    3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl, benzo[d]oxazol-5-yl,    3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl, benzo[b]thiophenyl, and    6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-3-yl, each optionally    substituted by one or more substitutents selected from the group    consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl,    haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl,    optionally substituted aralkyl, optionally substituted aralkenyl,    optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted cycloalkylalkenyl,    optionally substituted heterocyclyl, optionally substituted    heterocyclylalkyl, optionally substituted heterocyclylalkenyl,    optionally substituted heteroaryl, optionally substituted    heteroarylalkyl, optionally substituted heteroarylalkenyl,    —R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂,    —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,    —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,    —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹²    (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2),    —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂    (where t is 1 or 2); and-   R³ is a polycyclic heteroaryl containing more than 14 ring atoms    selected from the group consisting of    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl,    6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl,    6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl,    (Z)-dibenzo[b,f][1,4]thiazepin-11-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl,    6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl,    spiro[chromeno[4,3-c]pyridazine-5,1′-cyclopentane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2′-[1,3]dioxolane]-3-yl,    5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2′-[1,3]dioxolane]-3-yl,    6,7-dihydro-5H-benzo[2,3]thiepino[4,5-c]pyridazin-3-yl,    6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl,    5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2′-[1,3]dioxolane]-3-yl,    6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2′-[1,3]dioxane]-3-yl    and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl, each    optionally substituted by one or more substituents selected from the    group consisting of oxo, thioxo, cyano, nitro, halo, haloalkyl,    alkyl, optionally substituted cycloalkyl, optionally substituted    cycloalkylalkyl, optionally substituted aryl, optionally substituted    aralkyl, optionally substituted heteroaryl, optionally substituted    heterocyclyl, —R⁹—OR⁸, —R⁹—OC(O)—R⁸, —R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸,    —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR¹², —R⁹—N(R⁶)C(O)R⁸,    —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2), —R⁹—S(O)_(t)OR⁸ (where t is    1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or 2), and    —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2).

Another embodiment is the method where the compound of formula (Ib), asset forth above, is selected from the group consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(6-(4-(pyrrolidin-1-yl)piperidin-1-yl)-5-methylpyridin-3-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(4-(3,5-dimethylpiperazin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(2-(1-methylpiperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-1,2,4-triazole-3,5-diamine.

Another embodiment is the method where the compound of formula (Ib), asset forth above, is a compound of formula (Ib1):

wherein:

-   A is ═C(H)— or ═N—;-   each R^(2a) is independently selected from the group consisting of    —N(R^(12a))₂ and —N(R^(12a))C(O)R^(12a),-   or R^(2a) is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R²¹—C(O)OR²⁰,-   each R^(12a) is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl;-   R²⁰ is independently selected from the group consisting of hydrogen,    alkyl, alkenyl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl; and-   R²¹ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

In one embodiment of the methods of preventing, treating or managingcancer in a patient comprising administering to the patient in needthereof a therapeutically or prophylactically effective amount of an Axlinhibitor in combination with the administration of a therapeutically orprophylactically effective amount of one or more chemotherapeuticagents, the one or more chemotherapeutic agents is selected from thegroup consisting of antimetabolites, alkylating agents, coordinationcompounds, platinum complexes, DNA cross-linking compounds, inhibitorsof transcription enzymes, tyrosine kinase inhibitors, protein kinaseinhibitors, topoisomerase inhibitors, DNA minor-groove bindingcompounds, vinca alkyloids, taxanes, antitumor antibiotics, hormones,aromatase inhibitors, enzymes, growth factor receptors antibodies,cytokines, cell surface markers antibodies, HDAC inhibitors, HSP 90inhibitors, BCL-2 inhibitors, mTOR inhibitors, proteasome inhibitors andmonoclonal antibodies.

In another embodiment of methods of preventing, treating or managingcancer in a patient comprising administering to the patient in needthereof a therapeutically or prophylactically effective amount of an Axlinhibitor in combination with the administration of a therapeutically orprophylactically effective amount of one or more chemotherapeuticagents, the one or more chemotherapeutic agents are independentlyselected from the group consisting of mechlorothamine, cyclophosphamide,ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines,procarbazine, dacarbazine, temozolomide, busulfan, carmustine,lomustine, methotrexate, fluorouracil, capecitabine, cytarabine,gemcitabine, cytosine arabinoside, mecaptopurine, fludarabine,cladribine, thioguanine, azathioprine, vinblastine, vincristine,paclitaxel, docetaxel, colchicine, actinomycin D, daunorubicin,bleomycin, L-asparaginase, cisplatin, carboplatin, oxaliplatin,prednisone, dexamethasone, amino glutethimide, formestane, anastrozole,hydroxyprogesterone caproate, medroxyprogesterone, tamoxifen, amsacrine,mitoxantrone, topotecan, irinotecan, camptothecin, axtinib, bosutinib,cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib,lestaurtinib, nilotinib, semaxanib, sunitinib, vandetanib, vatalanib,anti-Her2 antibodies, interferon-α, interferon-γ, interleukin-2, GM-CSF,anti-CTLA-4 antibodies, rituximab, anti-CD33 antibodies, MGCD0103,vorinostat, 17-AAG, thalidomide, lenalidomide, rapamycin, CCI-779,sorafenib, doxorubicine, gemcitabine, melphalan, bortezomib, NPI052,gemtuzumab, alemtuzumab, ibritumomab tiuxaetan, tositumomab, iodine-131tositumomab, trastuzumab, bevacizumab, rituximab, and anti-TRAIL deathreceptor antibodies.

In another embodiment of methods of preventing, treating or managingcancer in a patient comprising administering to the patient in needthereof a therapeutically or prophylactically effective amount of an Axlinhibitor in combination with the administration of a therapeutically orprophylactically effective amount of one or more chemotherapeuticagents, the one or more chemotherapeutic agents are independentlyselected from the group consisting of paclitaxel, cyclophosphamide,5-fluorouracil, cisplatin, carboplatin, methotrexate and imitanib.

Preferably, one embodiment of the methods of preventing, treating ormanaging cancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, is the methodwherein the Axl inhibitor is a compound of formula (I) selected from thegroup consisting of:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(S)-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7s)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethyl    amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((5-chiorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-carb    oxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethyl    amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;    and the one or more chemotherapeutic agents is selected from the    group consisting of paclitaxel, cyclophosphamide, 5-fluorouracil,    cisplatin, carboplatin, methotrexate and imitanib.

Preferably, one embodiment of the methods of preventing, treating ormanaging cancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, is the methodwherein the Axl inhibitor is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.

Preferably, another embodiment of the methods of preventing, treating ormanaging cancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, is the methodwherein the Axl inhibitor is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.

Preferably, another embodiment of the methods of preventing, treating ormanaging cancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, is the methodwherein the Axl inhibitor is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.

Preferably, another embodiment of the methods of preventing, treating ormanaging cancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, is the methodwherein the Axl inhibitor is1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine.

Preferably, another embodiment of the methods of preventing, treating ormanaging cancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, is the methodwherein the Axl inhibitor is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine.

Preferably, another embodiment of the methods of preventing, treating ormanaging cancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, is the methodwherein the Axl inhibitor is1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(S)-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.

Preferably, in one embodiment, in any of the above embodiments of themethods of preventing, treating or managing cancer, preferablymetastatic cancer, in a patient comprising administering to the patientin need thereof a therapeutically or prophylactically effective amountof an Axl inhibitor in combination with the administration of atherapeutically or prophylactically effective amount of one or morechemotherapeutic agents, the one or more chemotherapeutic agents iscisplatin.

Preferably, in another embodiment, in any of the above embodiments ofthe methods of preventing, treating or managing cancer, preferablymetastatic cancer, in a patient comprising administering to the patientin need thereof a therapeutically or prophylactically effective amountof an Axl inhibitor in combination with the administration of atherapeutically or prophylactically effective amount of one or morechemotherapeutic agents, the one or more chemotherapeutic agents ispaclitaxel.

Preferably, in another embodiment, in any of the above embodiments ofthe methods of preventing, treating or managing cancer, preferablymetastatic cancer, in a patient comprising administering to the patientin need thereof a therapeutically or prophylactically effective amountof an Axl inhibitor in combination with the administration of atherapeutically or prophylactically effective amount of one or morechemotherapeutic agents, the one or more chemotherapeutic agents isimitanib.

In one embodiment of the methods of preventing, treating or managingcancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, the methodprevents metastatic cancer.

In another embodiment of the methods of preventing, treating or managingcancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, the methodtreats metastatic cancer.

In another embodiment of the methods of preventing, treating or managingcancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, the methodmanages metastatic cancer.

In one embodiment of the methods of preventing, treating or managingcancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, the Axlinhibitor is administered to the patient, preferably a human, in anamount of between about 1 mg/kg and about 100 mg/kg twice a day,preferably between about 5 mg/kg and about 80 mg/kg twice a day, evenmore preferably between about 5 mg/kg and about 25 mg/kg twice a day,and the chemotherapeutic agent is administered to the mammal in anamount of between about 1.0 mg/kg and about 10.0 mg/kg once a week,preferably between about 1.0 mg/kg and about 5 mg/kg once a week, evenmore preferably between about 1.0 mg/kg and 2.0 mg/kg once a week.

In one embodiment of the methods of preventing, treating or managingcancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, the Axlinhibitor is administered to the patient, preferably a human, at thesame time that the one or more chemotherapeutic agent is administered tothe patient.

In one embodiment of the methods of preventing, treating or managingcancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, the Axlinhibitor is administered to the patient, preferably a human,concurrently with the administration of the one or more chemotherapeuticagent is administered to the patient.

In another embodiment of the methods of preventing, treating or managingcancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, the Axlinhibitor is administered to the patient, preferably a human, prior tothe administration of the one or more chemotherapeutic agent isadministered to the patient.

In another embodiment of the methods of preventing, treating or managingcancer, preferably metastatic cancer, in a patient comprisingadministering to the patient in need thereof a therapeutically orprophylactically effective amount of an Axl inhibitor in combinationwith the administration of a therapeutically or prophylacticallyeffective amount of one or more chemotherapeutic agents, the Axlinhibitor is administered to the patient, preferably a human,sequentially to the administration of the one or more chemotherapeuticagent is administered to the patient.

Specific embodiments of the invention are described in more detail inthe following sections.

Utility and Testing of the Combination Therapies of the Invention

In the combination therapies of the invention, an Axl inhibitor,preferably a compound of formula (I), as set forth in the Summary of theInvention, is used as an active ingredient in combination with one ormore chemotherapeutic agents in the prevention, treatment or managementof one or more cancers, preferably metastatic cancers. Preferably, suchcombination therapies of the present invention will exert greater thanadditive effects, i.e., synergistic effects, as the mechanisms of actionemployed for the Axl inhibitor and the one or more chemotherapeuticagents may be different and each may act independently of one another.Accordingly, as used herein “combination therapy” refers to theadministration of an Axl inhibitor, preferably a compound of formula (I)as set forth above in the Summary of the Invention, in combination withthe administration of one or more chemotherapeutic agents for theprevention, treatment and management of one or more cancers, preferablymetastatic cancer. Unless the context makes clear otherwise,“combination therapy” may include simultaneous or sequentialadministration of the Axl inhibitor and the one or more chemotherapeuticagents, in any order, such as administering the Axl inhibitor at thesame time as the administration of the one or more chemotherapeuticagents, before the administration of the one or more chemotherapeuticagents or after the administration of the one or more chemotherapeuticagents. Unless the context makes clear otherwise, “combination therapy”may include the administration of dosage forms of an Axl inhibitorcombined with the dosage forms of one or more chemotherapeutic agents.Unless the context makes clear otherwise, “combination therapy” mayinclude different routes of administration for the Axl inhibitor and forthe one or more chemotherapeutic agent. Dosage forms, routes ofadministration and pharmaceutical compositions include, but are notlimited to, those described herein.

The oncogenic receptor tyrosine kinase, Axl, was recently identified,using a retroviral-based functional genetic screening protocol, as aregulator of haptotactic migration, which is a key event inangiogenesis. Inhibition of Axl by RNAi-mediated silencing blockedendothelial cell migration, proliferation and in vitro tube formation.These observations, which were disclosed at the American AssociationCancer Research General Meeting, Apr. 16-20, 2005, Anaheim, Calif., andThe 7th Annual Symposium on Anti-Angiogenic Agents, Feb. 10-13, 2005,San Diego, Calif.; (Requirement for The Receptor Tyrosine Kinase Axl inAngiogenesis and Tumor Growth, Holland, S. J. Powell, M. J., Franci, C.,Chan, E., Friera, A. M., Atchison, R., Xu, W., McLaughlin, J., Swift, S.E., Pali, E., Yam, G., Wong, S., Xu, X., Hu, Y., Lasaga, J., Shen, M.,Yu, S., Daniel, R., Hitoshi, Y., Bogenberger, J., Nor, J. E., Payan, D.G and Lorens, J. B), were substantiated by an in vivo study whichdemonstrated that stable, shRNAi-mediated Axl knockdown impairedformation of functional human blood vessels in a mouse model of humanangiogenesis. These observations were published in a peer reviewedjournal (Holland S J, Powell M J, Franci C, Chan E W, Friera A M,Atchison R E, McLaughlin J, Swift S E, Pali E S, Yam G, Wong S, LasagaJ, Shen M R, Yu S, Xu W, Hitoshi Y, Bogenberger J, Nor J E, Payan D G,Lorens J B. “Multiple roles for the receptor tyrosine kinase axl intumor formation”, Cancer Res. (2005) Vol. 65, pp 9294-303. Theseobservations are also disclosed in U.S. Published Patent Application2005/0118604 and European Patent Application 1 563 094, the disclosuresof which are incorporated in full by reference. Axl signaling,therefore, impacts multiple functions required for neovascularization invitro, and regulates angiogenesis in vivo. Regulation of thesepro-angiogenic processes required the catalytic activity of Axl. Thus,Axl-mediated angiogenic stimulation would be amenable to modulation by asmall molecule inhibitor of Axl catalytic activity.

Accordingly, Axl inhibitors contemplated for use in the combinationtherapies of the invention are disclosed in U.S. Published PatentApplication No. 20070213375, U.S. Published Patent Application No.20080153815, U.S. Published Patent Application No. 20080188454, U.S.Published Patent Application No. 20080176847, U.S. Published PatentApplication No. 20080188455, U.S. Published Patent Application No.20080182862, U.S. Published Patent Application No. 20080188474, U.S.Published Patent Application No. 20080117789, U.S. Published PatentApplication No. 20090111816, PCT Published Patent Application No. WO2007/0030680, PCT Published Patent Application No. WO 2008/045978, PCTPublished Patent Application No. WO 2008/083353, PCT Published PatentApplication No. WO 2008/0083357, PCT Published Patent Application No. WO2008/083367, PCT Published Patent Application No. WO 2008/083354, PCTPublished Patent Application No. WO 2008/083356, PCT Published PatentApplication No. WO 2008/080134, and PCT Published Patent Application No.WO 2009/054864, the disclosures of which are incorporated in full byreference herein in their entireties. The Axl inhibitors disclosed inPCT Published Patent Application No. WO 2008/083367 are particularlypreferred for use in the combination therapies of the invention.

The compounds of formula (I), as set forth above in the Summary of theInvention, are small molecule inhibitors of Axl catalytic activity, andare therefore useful in treating diseases and conditions which areassociated with Axl catalytic activity, including those diseases andconditions which are characterized by angiogenesis and/or cellproliferation. In particular, the compounds of formula (I) are useful intreating diseases and conditions which are alleviated by the modulationof Axl activity. Diseases and condtions which are alleviated by the“modulation of Axl activity” includes diseases and conditions which arealleviated by a decrease in Axl activity and diseases and conditionswhich are alleviated by an increase in Axl activity. Preferably suchdiseases and conditions are alleviated by a decrease in Axl activity(i.e., inhibition of Axl activity). Diseases and conditions which arealleviated by the modulation of Axl activity include, but are notlimited to, solid cancer tumors, including, but not limited to, breast,renal, endometrial, ovarian, thyroid, and non-small cell lung carcinoma,melanoma, prostate carcinoma, sarcoma, gastric cancer and uvealmelanoma; liquid tumors, including but not limited to, leukemias(particularly myeloid leukemias) and lymphomas; endometriosis, vasculardisease/injury (including but not limited to restenosis, atherosclerosisand thrombosis), psoriasis; visual impairment due to maculardegeneration; diabetic retinopathy and retinopathy of prematurity;kidney disease (including but not limited to glomerulonephritis,diabetic nephropathy and renal transplant rejection), rheumatoidarthritis; osteoarthritis, osteoporosis and cataracts.

In addition to the foregoing, the compounds of formula (I) are useful intreating diseases and conditions which are affected by the followingbiological processes: Invasion, migration, metastasis, or drugresistance as manifested in cancer; stem cell biology as manifested incancer; invasion, migration, adhesion, or angiogenesis as manifested inendometriosis; vascular remodeling as manifested in cardiovasculardisease, hypertension or vascular injury; bone homeostatasis asmanifested in osteoporosis or osteoarthritis; viral infection asmanifested, for example, in ebola virus infection; or differentiation asmanifested in obesity. The compounds of formula (I) may also be used tomodulate inflammatory processes by treating sepsis, acting as vaccineadjuvants, and/or potentiating the immune response in immuno-compromisedpatients.

In a preferred embodiment, the compounds of formula (I) are useful inpreventing, treating and managing cancers, preferably metastaticcancers.

The chemotherapeutic agents utilized in the combination therapies of theinvention may be general cytotoxic agents or may target a specificcellular molecule. Preferably, the chemotherapeutic agents utilized inthe combination therapies of the invention are useful in the prevention,treatment and management of one or more cancers, preferably metastaticcancers. Various classes of chemotherapeutic agents for the treatment ofcancer include, among others, antimetabolites, agents that react withDNA (e.g., alkylating agents, coordination compounds, platinumcomplexes, DNA cross-linking compounds, etc.), inhibitors oftranscription enzymes, tyrosine kinase inhibitors, topoisomeraseinhibitors, DNA minor-groove binding compounds, antimitotic agents(e.g., vinca alkyloids and taxanes), antitumor antibiotics, hormones,and enzymes. Exemplary DNA cross-linking drugs and alkylating agentsinclude, by way of example and not limitation, mechlorothamine,cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines,methylmelamines, procarbazine, dacarbazine, temozolomide, alkylsulfonates (e.g., busulfan), carmustine and lomustine. Exemplaryantimetabolites include, by way of example and not limitation, folateantagonists, e.g., methotrexate; pyrimidine antagonists, e.g.,fluorouracil, capecitabine, cytarabine, gemcitabine and cytosinearabinoside; and purine analogs, e.g., mecaptopurine, fludarabine,cladribine, thioguanine and azathioprine. Exemplary taxanes and vincaalkyloids include, by way of example and not limitation, vinblastine,vincristine, paclitaxel, docetaxel and colchicine. Exemplary antitumorantibiotics include, by way of example and not limitation, actinomycinD, daunorubicin, and bleomycin. An exemplary enzyme effective as ananti-neoplastic agent is L-asparaginase. Exemplary platinum complexesand coordination compounds include, by way of example and notlimitation, cisplatin (cis-diamminedichloridoplatinum(II) (CDDP)),carboplatin and oxaliplatin. Exemplary hormones and hormone-relatedcompounds include, by way of example and not limitation,adrenocorticosteroids, e.g., prednisone and dexamethasone; aromataseinhibitors, e.g., amino glutethimide, formestane, and anastrozole;progestin compounds, e.g., hydroxyprogesterone caproate andmedroxyprogesterone; and anti-estrogen compounds, e.g., tamoxifen.Exemplary topoisomerase inhibitors include, by way of example and notlimitation, amsacrine (m-AMSA), mitoxantrone, topotecan, irinotecan, andcamptothecin. Exemplary tyrosine kinase inhibitors include, by way ofexample and not limitation, axtinib, bosutinib, cediranib, dasatinib,erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib,semaxanib, sunitinib, vandetanib and vatalanib. Various derivativeanti-neoplastic agents that combine more than one anticancer activitymay also be used in the combination therapies of the invention. Forinstance, NSC290205 is a combination therapy compound incorporatingd-lactam derivative of androsterone and an alkylating agent based onN,N-bis(2-chloroethyl)aniline (Trafalis et al., 2005, Br. J. Haematol.128(3):343-50).

Other chemotherapeutics useful in the combination therapies of theinvention include, by way of example and not limitation, antibodiesdirected against growth factor receptors (e.g., anti-Her2); cytokinessuch as interferon-α and interferon-γ, interleukin-2, and GM-CSF; andantibodies for cell surface markers (e.g., anti-CTLA-4. anti-CD20(rituximab); anti-CD33). When antibodies against cell surface markersare used, a chemotherapeutic agent can be conjugated to it for specifictargeting to the tumor cell. Suitable conjugates include radioactivecompounds (e.g., radioactive metal bound to an antibody conjugatedchelator), cytotoxic compounds, and drug activating enzymes (e.g.,allinase, peptidases, esterases, catalytic antibodies, etc.) (see, e.g.,Arditti et al., 2005, Mol. Cancer Therap. 4(2):325-331, and U.S. Pat.No. 6,258,360, the disclosures of which are both incorporated herein infull by reference).

Additional chemotherapeutic agents useful in the combination therapiesof the invention include, but are not limited to, HDAC inhibitors (e.g.,MGCD0103 and vorinostat), HSP 90 inhibitors (e.g., 17-AAG), BCL-2inhibitors, thalidomide, lenalidomide, mTOR inhibitors (e.g., rapamycin,CCI-779), sorafenib, doxorubicine, gemcitabine, dexamethasone,melphalan, proteasome inhibitors (e.g., bortezomib, NPI052), monoclonalantibodies (e.g., gemtuzumab, alemtuzumab, ibritumomab tiuxaetan,tositumomab, iodine-131 tositumomab, trastuzumab, bevacizumab, rituximaband anti-TRAIL death receptor antibodies), and the like.

These and other chemotherapeutic agents useful in treating cancer aredescribed in the “Commonly Used Antineoplastic Drugs”, The Merck ManualsOnline Medical Library For HealthCare Professionals atwww.mercksource.com and Goodman and Gilmans The Pharmacological Basis ofTherapeutics, 10th Edition, Hardman, J. G. and Limbird, L. E. eds., pg.1381-1287, McGraw Hill, (1996), the disclosures of which both of whichare incorporated by reference herein.

In some embodiments, a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, can be used in the combination therapies of theinvention with a second kinase inhibitor that targets an oncogenickinase different from Axl. Examples include inhibitors of kinasesassociated with cell proliferative disorders such as, but not limited tothe inhibitors of the kinases, Aurora-A, AKT, CDK1/cyclinB,CDK2/cyclinA, CDK3/cyclinE, CDK5/p35, CDK6/cyclinD3, CDK7/cyclinH/MAT1,CHK1, CHK2, EGFR, c-RAF, RAS, cSRC, Yes, Fyn, Lck, Fes, Lyn, Bmx, FGFR3,GSK3α, GSK3β, P13, IGF-1R, MAPK2, MAPKAP-K2, JNK, MEK1, p70S6K, PAK2,PDGFRα, PDGFRβ, PDK1, PKA, PKCε, PKC, PKD2, VEGF, PRAK, PRK2, RET,ROCK-II, Rsk1, Rsk2, Rsk3, and SGK.

In some embodiments, the second kinase inhibitor is an inhibitor of Ablkinase. For example, chronic myelogenous leukemia is a myeloid neoplasmcharacterized by malignant proliferation of leukemic stem cells in thebone marrow. The majority of chronic myelogenous leukemia is associatedwith a cytogenetic abnormality defined by a reciprocal translocationt(9;22)(q34;q11). This chromosomal aberration results in generation of aBCR/ABL fusion protein with activated kinase activity. Inhibitors of thefusion protein kinase activity are effective in treating chronicmyelogenous leukemia although resistant forms may develop upon continuedtreatment. Use of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, in combination of Abl kinase inhibitors maylessen the chances of resistant cells by targeting a cellular processdifferent than that targeted by the kinase inhibitor alone. An exemplaryAbl kinase inhibitor is 2-phenylaminopyrimidine, also known as imatinibmesylate and GLEEVEC®. Thus, in some embodiments, a compound of formula(I), or a pharmaceutically acceptable salt thereof, can be used incombination with the Abl kinase inhibitor 2-phenylaminopyrimidine andits derivatives. In other embodiments, the Abl kinase inhibitor may bepyridol[2-3-d]pyrimidine and its derivatives, which was originallyidentified as inhibitors of Src kinase. In yet further embodiments, theAbl kinase inhibitor is tyrphostins and its derivatives (e.g.,adaphostin) which affects the association of the kinase with itssubstrates. Other Abl kinase inhibitors useful in the combinationtherapies of the present invention will be apparent to the skilledartisan.

In one embodiment of the combination therapies of the invention, the Axlinhibitor utilized therein works by the same mechanism as the one ormore chemotherapeutic agents utilized therein. In another embodiment ofthe combination therapies of the invention, the Axl inhibitor utilizedtherein works by a different mechanism than the one or morechemotherapeutic agents utilized therein.

The combination therapies of the invention are useful in preventing,treating or managing one or more cancers, preferably metastatic cancers.When a cancer spreads (metastasizes) from its original site (primarytumor) to another area of the body, it is termed “metastatic cancer”.Virtually all cancers have the potential to spread this way.Consequently, the combination therapies of the invention are useful inpreventing, treating or managing metastatic cancer wherein the primarytumor is one or more of the following cancers: Leukemias such as but notlimited to, acute leukemia, acute lymphocytic leukemia, acute myelocyticleukemias such as myeloblastic, promyelocytic, myelomonocytic,monocytic, erythroleukemia leukemias and myelodysplastic syndrome,chronic leukemias such as but not limited to, chronic myelocytic(granulocytic) leukemia, chronic lymphocytic leukemia, hairy cellleukemia; polycythemia vera; lymphomas such as but not limited toHodgkin's disease, non-Hodgkin's disease; multiple myelomas such as butnot limited to smoldering multiple myeloma, nonsecretory myeloma,osteosclerotic myeloma, plasma cell leukemia, solitary plasmacytoma andextramedullary plasmacytoma; Waldenstrom's macroglobulinemia; monoclonalgammopathy of undetermined significance; benign monoclonal gammopathy;heavy chain disease; bone and connective tissue sarcomas such as but notlimited to bone sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma,malignant giant cell tumor, fibrosarcoma of bone, chordoma, periostealsarcoma, soft-tissue sarcomas, angiosarcoma (hemangiosarcoma),fibrosarcoma, Kaposi's sarcoma, leiomyosarcoma, liposarcoma,lymphangiosarcoma, metastatic cancers, neurilemmoma, rhabdomyosarcoma,synovial sarcoma; brain tumors such as but not limited to, glioma,astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, nonglialtumor, acoustic neurinoma, craniopharyngioma, medulloblastoma,meningioma, pineocytoma, pineoblastoma, primary brain lymphoma; breastcancer, including, but not limited to, adenocarcinoma, lobular (smallcell) carcinoma, intraductal carcinoma, medullary breast cancer,mucinous breast cancer, tubular breast cancer, papillary breast cancer,primary cancers, Paget's disease, and inflammatory breast cancer;adrenal cancer such as but not limited to pheochromocytom andadrenocortical carcinoma; thyroid cancer such as but not limited topapillary or follicular thyroid cancer, medullary thyroid cancer andanaplastic thyroid cancer; pancreatic cancer such as but not limited to,insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secretingtumor, and carcinoid or islet cell tumor; pituitary cancers such as butlimited to Cushing's disease, prolactin-secreting tumor, acromegaly, anddiabetes insipius; eye cancers such as but not limited to ocularmelanoma such as iris melanoma, choroidal melanoma, and cilliary bodymelanoma, and retinoblastoma; vaginal cancers such as squamous cellcarcinoma, adenocarcinoma, and melanoma; vulvar cancer such as squamouscell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma,and Paget's disease; cervical cancers such as but not limited to,squamous cell carcinoma, and adenocarcinoma; uterine cancers such as butnot limited to endometrial carcinoma and uterine sarcoma; ovariancancers such as but not limited to, ovarian epithelial carcinoma,borderline tumor, germ cell tumor, and stromal tumor; esophageal cancerssuch as but not limited to, squamous cancer, adenocarcinoma, adenoidcyctic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma,sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell(small cell) carcinoma; stomach cancers such as but not limited to,adenocarcinoma, fungating (polypoid), ulcerating, superficial spreading,diffusely spreading, malignant lymphoma, liposarcoma, fibrosarcoma, andcarcinosarcoma; colon cancers; rectal cancers; liver cancers such as butnot limited to hepatocellular carcinoma and hepatoblastoma, gallbladdercancers such as adenocarcinoma; cholangiocarcinomas such as but notlimited to pappillary, nodular, and diffuse; lung cancers such asnon-small cell lung cancer, squamous cell carcinoma (epidermoidcarcinoma), adenocarcinoma, large-cell carcinoma and small-cell lungcancer; testicular cancers such as but not limited to germinal tumor,seminoma, anaplastic, classic (typical), spermatocytic, nonseminoma,embryonal carcinoma, teratoma carcinoma, choriocarcinoma (yolk-sactumor), prostate cancers such as but not limited to, adenocarcinoma,leiomyosarcoma, and rhabdomyosarcoma; genital cancers such as penilecancer; oral cancers such as but not limited to squamous cell carcinoma;basal cancers; salivary gland cancers such as but not limited toadenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma;pharynx cancers such as but not limited to squamous cell cancer, andverrucous; skin cancers such as but not limited to, basal cellcarcinoma, squamous cell carcinoma and melanoma, superficial spreadingmelanoma, nodular melanoma, lentigo malignant melanoma, acrallentiginous melanoma; kidney cancers such as but not limited to renalcell cancer, adenocarcinoma, hypernephroma, fibrosarcoma, transitionalcell cancer (renal pelvis and/or uterer); Wilms' tumor; bladder cancerssuch as but not limited to transitional cell carcinoma, squamous cellcancer, adenocarcinoma, carcinosarcoma. In addition, cancers includemyxosarcoma, osteogenic sarcoma, endotheliosarcoma,lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma,epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweatgland carcinoma, sebaceous gland carcinoma, papillary carcinoma andpapillary adenocarcinomas.

Whether metastases develop from a primary tumor depends on the complexinteraction of many tumor cell factors, including the type of primarytumor, the degree of maturity (differentiation) of the primary tumorcells, the location of the primary tumor and how long the primary tumorhas been present, as well as other incompletely understood factors.

The treatment of metastatic cancer depends on where the primary tumor islocated. When breast cancer spreads to the lungs, for example, itremains a breast cancer and the treatment is determined by themetastatic cancer origin within the breast, not by the fact that it isnow in the lung. About 5 percent of the time, metastatic cancer isdiscovered but the primary tumor cannot be identified. The treatment ofthese metastatic cancers is dictated by their location rather than theirorigin. Metastatic cancers are named by the tissue of the original tumor(if known). For example, a breast cancer that has spread to the brain iscalled metastatic breast cancer to the brain.

Metastases spread in three ways: by local extension from the tumor tothe surrounding tissues, through the bloodstream to distant sites orthrough the lymphatic system to neighboring or distant lymph nodes. Eachkind of cancer may have a typical route of spread.

Tissues which are particularly susceptible to metastatic cancer are thebrain, liver, bone and lung, although all tissues of the body may beaffected. Any cancer may spread to the brain, although the most commonto do so are lung and breast cancer. The most common cancer tometastasize to the liver is colon or other gastrointestinal cancer. Themost common cancers to spread to the bones are prostate, lung and breastcancer. Metastases to the lung are common for many types of cancer.

In a preferred embodiment of the invention, the specific property ofmetastasis is targeted using the combination therapies described herein.In some embodiments, an Axl inhibitor, preferably a compound of formula(I) as set forth above in the Summary of the Invention, in combinationwith one or more chemotherapeutic agents, can be used to treatmetastasis arising from a primiary tumor in various tissues of the body,including, but not limited to, primary tumors of the bone, breast,respiratory tract, brain, reproductive organs, digestive tract, urinarytract (e.g., bladder), eye, liver, skin, head, neck, thyroid,parathyroid, and metastatic forms thereof. In one embodiment, themetastasis to be treated by the combination therapies of the inventionis lung and/or liver metastasis arising from a primary tumor of thebreast.

The combination therapies of the invention are also useful in treatingcertain celluar proliferative disorders. Such disorders include, but arenot limited to, the following:

a) proliferative disorders of the breast, which include, but are notlimited to, invasive ductal carcinoma, invasive lobular carcinoma,ductal carcinoma, lobular carcinoma in situ and metastatic breastcancer;

b) proliferative disorders of the skin, which include, but are notlimited to, basal cell carcinoma, squamous cell carcinoma, malignantmelanoma and Karposi's sarcoma;

c) proliferative disorders of the respiratory tract, which include, butare not limited to, small cell and non-small cell lung carcinoma,bronchial adema, pleuropulmonary blastoma and malignant mesothelioma;

d) proliferative disorders of the brain, which include, but are notlimited to, brain stem and hyptothalamic glioma, cerebellar and cerebralastrocytoma, medullablastoma, ependymal tumors, oligodendroglial,meningiomas and neuroectodermal and pineal tumors;

e) proliferative disorders of the male reproductive organs, whichinclude, but are not limited to, prostate cancer, testicular cancer andpenile cancer;

f) proliferative disorders of the female reproductive organs, whichinclude, but are not limited to, uterine cancer (endometrial), cervical,ovarian, vaginal, vulval cancers, uterine sarcoma and ovarian germ celltumor;

g) proliferative disorders of the digestive tract, which include, butare not limited to, anal, colon, colorectal, esophageal, gallbladder,stomach (gastric), pancreatic cancer, pancreatic cancer—Islet cell,rectal, small-intestine and salivary gland cancers;

h) proliferative disorders of the liver, which include, but are notlimited to, hepatocellular carcinoma, cholangiocarcinoma, mixedhepatocellular cholangiocarcinoma, primary liver cancer and metastaticliver cancer;

i) proliferative disorders of the eye, which include, but are notlimited to, intraocular melanoma, retinoblastoma, and rhabdomyosarcoma;

j) proliferative disorders of the head and neck, which include, but arenot limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngealcancers, and lip and oral cancer, squamous neck cancer, metastaticparanasal sinus cancer;

k) proliferative disorders of lymphocytic cells, which include, but arenot limited to, various T cell and B cell lymphomas, non-Hodgkinslymphoma, cutaneous T cell lymphoma, Hodgkins disease, and lymphoma ofthe central nervous system;

l) leukemias, which include, but are not limited to, acute myeloidleukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia,chronic myelogenous leukemia, and hairy cell leukemia,

m) proliferative disorders of the thyroid, which include, but are notlimited to, thyroid cancer, thymoma, malignant thymoma, medullarythyroid carcinomas, papillary thyroid carcinomas, multiple endocrineneoplasia type 2A (MEN2A), pheochromocytoma, parathyroid adenomas,multiple endocrine neoplasia type 2B (MEN2B), familial medullary thyroidcarcinoma (FMTC) and carcinoids;

n) proliferative disorders of the urinary tract, which include, but arenot limited to, bladder cancer;

o) sarcomas, which include, but are not limited to, sarcoma of the softtissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma;

p) proliferative disorders of the kidneys, which include, but are notlimited to, renal cell carcinoma, clear cell carcinoma of the kidney;and renal cell adenocarcinoma;

q) precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acutelymphoblastic leukemia), B-cell chronic lymphocytic leukemia/smalllymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma, splenic marginal zone B-cell lymphoma, hairy cell leukemia,plasma cell myeloma/plasmacytoma, extranodal marginal zone B-celllymphoma of MALT type, nodal marginal zone B-cell lymphoma, follicularlymphoma, mantle-cell lymphoma, diffuse large B-cell lymphoma,mediastinal large B-cell lymphoma, primary effusion lymphoma andBurkitt's lymphoma/Burkitt cell leukemia

(r) precursor T-lymphoblastic lymphoma/leukemia (precursor T-cell acutelymphoblastic leukemia), T-cell prolymphocytic leukemia, T-cell granularlymphocytic leukemia, aggressive NK-cell leukemia, adult T-celllymphoma/leukemia (HTLV-1), extranodal NK/T-cell lymphoma, nasal type,enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, mycosisfungoides/Sezary syndrome, anaplastic large-cell lymphoma, T/null cell,primary cutaneous type, peripheral T-cell lymphoma, not otherwisecharacterized, angioimmunoblastic T-cell lymphoma, anaplastic large-celllymphoma, T/null cell, and primary systemic type;

(s) nodular lymphocyte-predominant Hodgkin's lymphoma, nodular sclerosisHodgkin's lymphoma (grades 1 and 2), lymphocyte-rich classical Hodgkin'slymphoma, mixed cellularity Hodgkin's lymphoma, and lymphocyte depletionHodgkin's lymphoma;

(t) myelogenous leukemia (e.g., Philadelphia chromosome positive(t(9;22)(qq34;q11)), multiple myeloma, chronic neutrophilic leukemia,chronic eosinophilic leukemia/hypereosinophilic syndrome, chronicidiopathic myelofibrosis, polycythemia vera, essential thrombocythemia,chronic myelomonocytic leukemia, atypical chronic myelogenous leukemia,juvenile myelomonocytic leukemia, refractory anemia with ringedsideroblasts and without ringed sideroblasts, refractory cytopenia(myelodysplastic syndrome) with multilineage dysplasia, refractoryanemia (myelodysplastic syndrome) with excess blasts, 5q-syndrome, andmyelodysplastic syndrome with t(9;12)(q22;p12);

(u) AML with t(8;21)(q22;q22), AML1(CBF-alpha)/ETO, acute promyelocyticleukemia (AML with t(15;17)(q22;q11-12) and variants, PML/RAR-alpha),AML with abnormal bone marrow eosinophils (inv(16)(p13q22) or t(16;16)(p13;q11), CBFb/MYH11X), and AML with 11q23 (MLL) abnormalities, AMLminimally differentiated, AML without maturation, AML with maturation,acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroidleukemia, acute megakaryocytic leukemia, acute basophilic leukemia, andacute panmyelosis with myelofibrosis.

It is to be understood that the descriptions of proliferative disordersis not limited to the conditions described above, but encompasses otherdisorders characterized by uncontrolled growth and malignancy. It isfurther understood that proliferative disorders include variousmetastatic forms of the primary tumor and cancer types described herein.The combination therapies of the invention may be tested foreffectiveness against these disorders, particularly various metastaticforms of the primary tumor, and a therapeutically effective regimenestablished. Effectiveness, as further described below, includesreduction or remission of the metastatic tumors, decreases in the rateof cell proliferation, or cytostatic or cytotoxic effect on metastaticcancer cell growth.

The antiproliferative effect of a combination therapy of the inventionmay be assessed by administering the active ingredients of thecombination therapy to a cultured tumor cell line. In the context of anin vitro assay, administration of an active ingredient may be simplyachieved by contacting the cells in culture with the active ingredientin amounts effective to inhibit cell proliferation. Alternatively, theantiproliferative effect of a combination therapy of the invention maybe assessed by administering the active ingredients of the combinationtherapy to an animal in an approved in vivo model for cellproliferation.

Examples of tumor cell lines derived from human tumors and available foruse in the in vivo studies include, but are not limited to, leukemiacell lines (e.g., CCRF-CEM, HL-60(TB), K-562, MOLT-4, RPM1-8226, SR,P388 and P388/ADR); non-small cell lung cancer cell lines (e.g.,A549/ATCC, EKVX, HOP-62, HOP-92, NCI-H226, NCI-H23, NCI-H322M, NCI-H460,NCI-H522 and LXFL 529); small cell lung cancer cell lines (e.g., DMS 114and SHP-77); colon cancer cell lines (e.g., COLO 205, HCC-2998, HCT-116,HCT-15, HT29, KM12, SW-620, DLD-1 and KM20L2); central nervous system(CNS) cancer cell lines (e.g., SF-268, SF-295, SF-539, SNB-19, SNB-75,U251, SNB-78 and XF 498); melanoma cell lines (e.g., LOX I MVI,MALME-3M, M14, SK-MEL-2, SK-MEL-28, SK-MEL-5, UACC-257, UACC-62,RPMI-7951 and M19-MEL); ovarian cancer cell lines (e.g., IGROV1,OVCAR-3, OVCAR-4, OVCAR-5, OVCAR-8 and SK-OV-3); renal cancer cell lines(e.g., 786-0, A498, ACHN, CAKI-1, RXF 393, SN12C, TK-10, UO-31, RXF-631and SN12K1); prostate cancer cell lines (e.g., PC-3 and DU-145); breastcancer cell lines (e.g., MCF7, NCI/ADR-RES, MDA-MB-231/ATCC, HS 578T,MDA-MB-435, BT-549, T-47D and MDA-MB-468); and thyroid cancer cell lines(e.g., SK-N-SH).

The combination therapies of the invention can be tested for thetreatment of leukemias and lymphomas by testing the combination therapyin the xenograft in SCID mouse model using human Axl-expressing cancercell lines including, but not limited to, HeLa, MDA-MB-231, SK-OV-3,OVCAR-8, DU145, H1299, ACHN, A498 and Caki-1. In addition, thecombination therapy may be tested for its use in treating leukemias inthe xenograft in SCID or nu/nu mouse model using human Axl-expressingAML and CML leukemia cell lines.

The combination therapies of the invention may be tested for efficacy inpreventing, treating or managing metastatic cancers in known animalmodels of metastatic cancer, such as the Mouse 4T1 Breast Tumor Model(see Pulaski, B. A. et al., Current Protocols in Immunology (2000),20.2.1-20.2.16), the disclosure of which is incorporated herein in fullin its entirety, or variations thereof.

Pharmaceutical Compositions, Dosages and Administration of theCombination Therapies of the Invention

Pharmaceutical compositions of Axl inhibitors and other chemotherapeuticagents used in the combination therapies of the invention are known orcan be prepared according to methods known to one skilled in the art.For example, methods of preparing and formulating pharmaceuticalcompositions of the Axl inhibitors of formula (I), as set forth above inthe Summary of the invention, are disclosed in PCT Published PatentApplication No. 2008/083367, which is incorporated in full herein in itsentirety, as well as methods of administration.

In general, the amount of an Axl inhibitor, preferably a compound offormula (I), as set forth in the Summary of the Invention, or the amountof one or more chemotherapeutic agents which will be effective in thetreatment, prevention or management of metastatic cancer in thecombination therapies of the invention can be determined by standardresearch techniques. For example, the dosage amount of each activeingredient in a combination therapy of the invention which will beeffective in the treatment, prevention or management of metastaticcancer can be determined by administering the combination therapy to ananimal model such as the ones described herein or by one known to oneskilled in the art. In addition, in vivo assays may optionally beemployed to help identify optimal dosage ranges of each activeingredient in a combination therapy of the invention.

Selection of the preferred prophylactically or therapeutically effectivedose of an active ingredient used in the combination therapies of theinvention can be determined (e.g., by clinical trials) by a skilledartisan based upon the consideration of several factors, including theactivity of the specific compound employed; the metabolic stability andlength of action of the compound; the age, body weight, general health,sex, and diet of the patient; the mode and time of administration; therate of excretion; the drug combination; and the severity of themetastatic cancer.

The precise dose of either the Axl inhibitor or the one or morechemotherapeutic agents used in the combination therapies of theinvention will also depend on the route of administration and theseriousness of the metastatic cancer and should be decided according tothe judgment of the medical practitioner and each patient'scircumstances. Effective doses may be extropolated from dose-responsecurves derived from in vitro or animal model test systems.

For example, a therapeutically effective daily dose for an Axlinhibitor, i.e., a compound of formula (I), as set forth above in theSummary of the Invention, is (for a 70 kg mammal) from about 0.001 mg/kg(i.e., 0.07 mg) to about 100 mg/kg (i.e., 7.0 gm); preferably atherapeutically effective dose is (for a 70 kg mammal) from about 0.01mg/kg (i.e., 0.7 mg) to about 50 mg/kg (i.e., 3.5 gm); more preferably atherapeutically effective dose is (for a 70 kg mammal) from about 1mg/kg (i.e., 70 mg) to about 25 mg/kg (i.e., 1.75 gm).

Dosages, routes of administration and recommended usage of thechemotherapeutic agents used in the combination therapies of theinvention are known in the art and often described in such literature asthe Physician's Desk Reference (current edition). In addition, typicaldoses of certain known chemotherapeutic agents are provided in U.S. Pat.No. 7,351,729, the relevant section of which is incorporated in full byreference herein.

Preferably, the invention provides for any method of administering lowerdoses of the one or more chemotherapeutic agents used in the combinationtherapies of the invention than previously known to be effective for theprevention, treatment and management of metastatic cancer. Even morepreferably, lower doses of the one or more chemotherapeutic agents areadministered in the combination therapies of the invention with lowerdoses of the Axl inhibitor.

In the combination therapies of the invention, an Axl inhibitor isadministered simultaneously with, prior to, or after administration ofone or more other chemotherapeutic agents, as described herein, by thesame route of administration or by different routes. Such combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains an Axl inhibitor and one or more additionalchemotherapeutic agents, as well as administration of the Axl inhibitorand each chemotherapeutic agent in its own separate pharmaceuticaldosage formulation. For example, the Axl inhibitor and the other one ormore chemotherapeutic agents can be administered to the patient togetherin a single oral dosage composition such as a tablet or capsule, or eachagent can be administered in separate oral dosage formulations. Whereseparate dosage formulations are used, the Axl inhibitor and the one ormore chemotherapeutic agents can be administered to the patient atessentially the same time, i.e., concurrently, or at separatelystaggered times, i.e., sequentially. All such combinations ofadministration are encompassed by the combination therapies of theinvention.

In certain embodiments of the combination therapies of the invention,the Axl inhibitor is administered to a patient, preferably a human,concurrently with one or more chemotherapeutic agents useful for thetreatment of cancer. The term “concurrently” is not limited to theadministration of the active ingredients (i.e., the Axl inhibitor andthe one or more chemotherapeutic agents) at exactly the same time, butrather it is meant that the Axl inhibitor and the other chemotherapeuticagent are administered to a patient in a sequence and within a timeinterval such that the Axl inhibitor can act together with the otherchemotherapeutic agent to provide an increased benefit than if they wereadministered otherwise. For example, each active ingredient of thecombination therapies of the invention may be administered at the sametime or sequentially in any order at different points in time; however,if not administered at the same time, they should be administeredsufficiently close in time so as to provide the desired therapeutic orprophylactic effect. Each active ingredient can be administeredseparately, in any appropriate form and by any suitable route. Invarious embodiments, the active ingredients are administered less than 1hour apart, at about 1 hour apart, at about 1 hour to about 2 hoursapart, at about 2 hours to about 3 hours apart, at about 3 hours toabout 4 hours apart, at about 4 hours to about 5 hours apart, at about 5hours to about 6 hours apart, at about 6 hours to about 7 hours apart,at about 7 hours to about 8 hours apart, at about 8 hours to about 9hours apart, at about 9 hours to about 10 hours apart, at about 10 hoursto about 11 hours apart, at about 11 hours to about 12 hours apart, nomore than 24 hours apart or no more than 48 hours apart. In preferredembodiments, two or more active ingredients are administered within thesame patient visit.

In other embodiments, the active ingredients are administered at about 2to 4 days apart, at about 4 to 6 days apart, at about 1 week part, atabout 1 to 2 weeks apart, or more than 2 weeks apart. In preferredembodiments, the active ingredients are administered in a time framewhere both active ingredients are still prophylactically andtherapeutically active. One skilled in the art would be able todetermine such a time frame by determining the half life of theadministered active ingredients.

In certain embodiments, the active ingredients of the invention arecyclically administered to a patient. Cycling therapy involves theadministration of a first active ingredient, such as the Axl inhibitor,for a period of time, followed by the administration of the secondand/or third active ingredient for a period of time and repeating thissequential administration. Cycling therapy can reduce the development ofresistance to one or more of the therapies, avoid or reduce the sideeffects of one of the therapies, and/or improves the efficacy of thetreatment.

In certain embodiments, the active ingredients are administered in acycle of less than about 3 weeks, about once every two weeks, about onceevery 10 days or about once every week. One cycle can comprise theadministration of an active ingredient by infusion over about 90 minutesevery cycle, about 1 hour every cycle, about 45 minutes every cycle.Each cycle can comprise at least 1 week of rest, at least 2 weeks ofrest, at least 3 weeks of rest. The number of cycles administered isfrom about 1 to about 12 cycles, more typically from about 2 to about 10cycles, and more typically from about 2 to about 8 cycles.

In yet other embodiments, the active ingredients of the combinationtherapies of the invention are administered in metronomic dosingregimens, either by continuous infusion or frequent administrationwithout extended rest periods. Such metronomic administration caninvolve dosing at constant intervals without rest periods. Typically thechemotherapeutic agents, in particular cytotoxic agents, are used atlower doses. Such dosing regimens encompass the chronic dailyadministration of relatively low doses for extended periods of time. Inone embodiment, the use of lower doses of the chemotherapeutic agent canminimize toxic side effects and eliminate rest periods. In certainembodiments, the active ingredients are administered by chronic low-doseor continuous infusion ranging from about 24 hours to about 2 days, toabout 1 week, to about 2 weeks, to about 3 weeks to about 1 month toabout 2 months, to about 3 months, to about 4 months, to about 5 months,to about 6 months. The scheduling of such dose regimens can beoptimalized by the skilled oncologist.

In other embodiments, the active ingredients are administeredconcurrently to a patient such that doses of the chemotherapeutic agentare administered separately yet within a time interval such that the Axlinhibitor can work together with the chemotherapeutic agent. Forexample, the chemotherapeutic agent may be administered one time perweek and the Axl inhibitor may be administered every day. In otherwords, the dosing regimens for the active ingredients are carried outconcurrently even if the active ingredients are not administeredsimultaneously or within the same patient visit.

In a preferred embodiment, the Axl inhibitor is administered every dayto the patient and the one or more chemotherapeutic agent isadministered once a week.

Preparation of the Compounds of Formula (I)

Compounds of formula (I) utilized in the combination therapies of theinvention can be made using organic synthesis techniques known to thoseskilled in the art, as well as by the methods described in PCT PublishedPatent Application No. 2008/083367, which is incorporated herein byreference in its entirety. Specific examples of the compounds of formula(I) can be found in this publication.

Alternatively, certain compounds of formula (I), as set forth above inthe Summary of the Invention, can be made by the methods disclosedherein. In particular, the following Reaction Schemes illustrate methodsto make compounds of formula (I) having the following formula (Ia1):

wherein:

-   A is ═C(H)— or ═N—;-   each R^(2a) is independently selected from the group consisting of    —N(R^(12a))₂ and —N(R^(12a))C(O)R^(12a),-   or R^(2a) is an N-heterocyclyl optionally substituted by one or more    substituents selected from the group consisting of halo and    —R²¹—C(O)OR²⁰,-   each R^(12a) is independently selected from the group consisting of    hydrogen, alkyl, alkenyl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl;-   R²⁰ is independently selected from the group consisting of hydrogen,    alkyl, alkenyl, optionally substituted aralkyl, optionally    substituted cycloalkyl, optionally substituted cycloalkylalkyl,    optionally substituted heteroaryl and optionally substituted    heteroarylalkyl; and-   R²¹ is independently selected from the group consisting of a direct    bond or an optionally substituted straight or branched alkylene    chain;-   as an isolated stereoisomer or mixture thereof, or a    pharmaceutically acceptable salt thereof.

It is understood that one of ordinary skill in the art would be able tomake the compounds of formula (Ia1) by methods similar to the methodsdescribed herein or by methods known to one of ordinary skill in theart. It is also understood that one of ordinary skill in the art wouldbe able to make in a similar manner as described below other compoundsof formula (Ia1) and the compounds of formula (Ib1), as set forth abovein the Embodiments section, not specifically illustrated below by usingthe appropriate starting components and modifying the parameters of thesynthesis as needed.

It is also understood that in the following Reaction Schemes andthroughout this description, combinations of substituents and/orvariables of the depicted formulae are permissible only if suchcontributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocesses described below the functional groups of intermediatecompounds may need to be protected by suitable protecting groups. Suchfunctional groups include hydroxy, amino, mercapto and carboxylic acid.Suitable protecting groups for hydroxy include trialkylsilyl ordiarylalkylsilyl (for example, t-butyldimethylsilyl,t-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, andthe like. Suitable protecting groups for amino, amidino and guanidinoinclude benzyl, t-butoxycarbonyl, benzyloxycarbonyl, and the like.Suitable protecting groups for mercapto include —C(O)—R″ (where R″ isalkyl, aryl or arylalkyl), p-methoxybenzyl, trityl and the like.Suitable protecting groups for carboxylic acids include alkyl, aryl orarylalkyl esters.

Protecting groups may be added or removed in accordance with standardtechniques, which are known to one of ordinary skill in the art and asdescribed herein.

The use of protecting groups is described in detail in Greene, T. W. andP. G. M. Wuts, Greene's Protective Groups in Organic Synthesis (1999),3rd Ed., Wiley. As one of skill in the art would appreciate, theprotecting group may also be a polymer resin such as, but not limitedto, a Wang resin, Rink resin or a 2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”.

In general, starting components may be obtained from sources such asSigma Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific,TCI, and Fluorochem USA, etc. or synthesized according to sources knownto those skilled in the art (see, for example, Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 5th edition (Wiley,December 2000)) or prepared as described in this invention. ¹H NMRspectra were recorded in CDCl₃, DMSO-d₆, CD₃OD, Acetone-d₆ withtrimethylsilane (TMS) as internal reference using Gemini 300 MHzinstrument. Reagents and solvents were purchased from commercial sourcesand used without further purification. Flash column chromatography wasconducted using silica gel (230-400 mesh) under a positive pressure ofnitrogen. Waters LCMS instruments were used for recording LCMS spectrafor purity and mass determinations. Deionized water was used to dilutethe reactions and wash the products. Brine used was prepared bydissolving sodium chloride into deionized water to saturation point.

Compounds of formula (Ia1), as described above, are generally preparedas illustrated below in Reaction Scheme 1 where A and R^(2a) are asdescribed above for the compounds of formula (Ia1) and Ph is a phenylgroup:

Compounds of formula (A), formula (B) and formula (D) are commerciallyavailable or can be prepared by methods known to one skilled in the artor by methods disclosed herein.

In general, compounds of formula (Ia1) are prepared, as set forth byReaction Scheme 1, by first treating diphenyl cyanocarbonimidate (A)(where the phenyl groups therein may be replaced with other suitablegroups or suitably substituted groups known to one skilled in the art)(1.1 equiv) with an equivalent amount of an aniline of formula (B) in anpolar solvent, including, but not limited to, isopropyl alcohol, atambient temperatures overnight. The diarylisourea product of formula (C)generally precipitates and isolation can be accomplished via filtration,washing with an appropriate solvent, and drying. Hydrazine hydrate offormula (D) (2 equivalents) is added to a slurry of the compound offormula (C) in an alcohol or other appropriate solvent. Generally, thering formation reaction occurs at ambient temperature and the producttriazole of formula (Ia1) can be isolated by standard isolationtechniques.

Compounds of formula (Ib1), as set forth above in the Embodimentssection, can be prepared using the synthetic route outlined in ReactionScheme 1 in varying amounts depending on the steric and electronicnature of the starting materials as well as the particular reactionconditions employed. In some instances, compounds of formula (Ib1) areisolated as minor isomers along with compounds of formula (Ia1) as majorisomers, e.g., during column chromatography as described herein.

Compounds of formula (C-1) are compounds of formula (C), as set forthabove in Reaction Scheme 1, where R^(2a) is pyrrolidin-1-yl. They can beprepared according to the method described below in relation to ReactionScheme 2:

Compounds of formula (Ca) and formula (A) are commercially available orcan be prepared according to methods described herein or known to oneskilled in the art. Compounds of formula (Ba) are compounds of formula(B), as set forth above in Reaction Scheme 1.

In general, compounds of formula (C-1) are prepared, for example, as setforth above in Reaction Scheme 2, by nitration of the benzo[7]annuleneof formula (Ca) to form the nitro compound of formula (Cb). Reductiveamination of the keto group in the ketone of formula (Cb) yields thepyrrolidine-substituted compound of formula (Cc). Reduction of the nitrogroup of the pyrrolidine-substituted compound of formula (Cc), forexample, by catalytic hydrogenation, gives the aniline of formula (Ba).Reaction of the aniline of formula (Ba) with diphenyl cyanocarbonimidateof formula (A) yields the compound of formula (C-1). Compounds offormula (C-1) are enantiomeric. The enantiomers of compound (C-1), andsimilar compounds of the invention, can be isolated, for example, bychiral phase HPLC.

Stereoselective amination of certain cyclic ketones, such as thecompounds of formula (Cb) as set forth above, can be very challenging orimpossible. Accordingly, the following describes one method of makingcompounds of formula (Ia1) and (Ib1) using transaminases to produceenantiomerically pure primary amines from cyclic ketones, particularlyfrom cyclic ketones fused to a substituted aromatic ring.

Transaminases (also known as amino transferases) are enzymes thatcatalyze a transamination reaction between an amino-donor molecule (suchas an amine or amino acid) and an amino-acceptor molecule (such as aketone or an α-keto acid). Specifically, enzymatic transaminationinvolves removing the amino group from the amino-donor molecule (leavingbehind a carbonyl group) and transferring the amino group to theamino-acceptor molecule (or α-keto acid) by converting the ketone moietytherein to an amine (or an amino acid). A description of transaminasesand their use in stereo-selective synthesis can be found in“Transminations. Enzyme Catalysis in Organic Synthesis (2^(nd) Edition)(2002)”, by J. David Rozzell and Andreas S. Bommarius, pp. 873-893,which is incorporated in full by reference herein.

Transaminases are particularly suitable for the enzymatic synthesis ofchiral amines from the corresponding ketone precursors. Commerciallyavailable transaminases can be used to achieve a chiral enzymaticamination of a desired starting material in the preparation of thecompounds of the invention. In particular, a ketone of the followingformula (i) where n and m are the same and are 0, 1 or 2 and R is nitro,halo or —C(O)OR^(12a) (where R^(12a) is as described above for thecompounds of formula (Ia1)) can be converted under suitable conditionsto the corresponding (S)-enantiomer and (R)-enantiomer wherein thecarbon to which the amino group is attached is either in the (S) or the(R) configuration, respectively, by utilizing a (S)-specifictransaminase and an amino donor molecule, such as L-alanine, or a(R)-specific transaminase and an amino donor molecule, such asL-alanine, as shown below:

One of ordinary skill in the art would appreciate that the amino groupon the (S)-enantiomer and the (R)-enantiomer can be furtherfunctionalized by standard procedures known to one skilled in the art.For example, treatment of the above (S)-enantiomer with1,4-dibromobutane under the appropriate alkylation conditions willresult in the amino group being converted to a 1-pyrrolidinyl groupwithout racemization of the chiral center. Alternatively, treatment ofthe above (S)-enantiomer with an appropriate acylating agent with resultin the amino group being acylated accordingly, and so forth.

Utilizing the appropriate transaminase to convert the cyclic ketone offormula (i) into the appropriate enantiomer, the appropriate enantiomercan be isolated in greater than 80% ee and preferably greater than 90%ee.

The following Reaction 3, where the compound of formula (Cb-1) is acompound of formula (i) as described above and PG represents a nitrogenprotecting group, illustrates a method of preparing a chiral compound offormula (Ia1) utilizing a transaminase as described above:

Compounds of formula (Cb-1) are commercially available, or can beprepared by methods known to one skilled in the art. Compounds offormula (D-1) can be prepared according to methods known to one skilledin the art or by methods disclosed herein. The (S)-specific transaminaseis commercially available from Codexis. Preferably the (S)-specifictransaminase is ATA-103 from Codexis.

In general, compounds of formula (Ia1-1) are prepared by the methoddisclosed above in Reaction Scheme 3 by first converting the ketone offormula (Cb-1) into the chiral compound of formula (Cb-2) wherein theamino group from an amino donor molecule, preferably L-alanine, istransferred to the ketone of formula (Cb-1) through an enzymatictransamination reaction under suitable conditions. In particular, theketone of formula (Cb-1) is treated with a excess molar amount of anamino donor molecule in the the presence of a catalytic amount of atransaminase, preferably a (S)-specific transaminase, and astoichiometric or excess stoichiometric amount of a pyruvate reductasemixture that reduces (deactivates) the 2-keto acid side product, therebydriving the reaction into the desired direction. Preferably the pyruvatereductase mixture is PRM-102 from Codexix. The reaction is conducted atambient temperature, at a pH of between about 7.5 and about 8.0, and fora period of time of between about 24 hours and about 6 days, preferablyfor about 4 days. The chiral compound of formula (Cb-2) is isolated fromthe reaction mixture by standard isolation techniques known to oneskilled in the art.

Alternatively, the transamination reaction can be driven to completionby coupling the reaction to a second reaction that consumes the 2-ketoacid by-product in an essentially irreversible step, as described inmore detail in “Transminations. Enzyme Catalysis in Organic Synthesis(2^(nd) Edition) (2002)”, by J. David Rozzell and Andreas S. Bommarius,pp. 873-893.

The amino group of the chiral compound of formula (Cb-2) is thenprotected by standard nitrogen protecting procedures to yield thecompound of formula (Cb-3), which is isolated from the reaction mixtureby standard isolation techniques known to one skilled in the art. Thecompound of formula (Cb-3) is then treated to standard reducingconditions, such as treatment with H₂/Pd, to produce the correspondinganiline compound of formula (Cb-4), which is isolated from the reactionmixture by standard isolation techniques known to one skilled in theart. The compound of formula (Cb-4) is then treated with diphenylcyanocarbonimidate of formula (A) to produce the compound of formula(Cb-5), which is isolated from the reaction mixture by standardisolation techniques known to one skilled in the art.

The compound of (Cb-5) is then treated with a compound of formula (D-1)in the presence of an aprotic solvent, preferably toluene, at atemperature of between about 80° C. and about 100° C. for a period oftime of between about 12 hours and about 36 hours, preferably for about24 hours, to yield a compound of formula (Ia1-1), which is isolated fromthe reaction mixture by standard isolation techniques known to oneskilled in the art. Compound of formula (Ia1-1) is a compound of formula(Ia1), as set forth above.

The protecting group on the compound of formula (Ia1-1) can be removedunder standard deprotecting conditions known to one skilled in the art,such as acid hydrolysis, to produce a compound of formula (Ia1-2), whichis isolated from the reaction mixture by standard isolation techniquesknown to one skilled in the art. The compound of formula (Ia1-2) can befurther treated with the appropriate aldehyde or ketone under standardreductive amination conditions to yield a compound of formula (Ia1-3),which is isolated from the reaction mixture by standard isolationtechniques known to one skilled in the art.

Compounds of formula (D-1) utilized in Reaction Scheme 3 above arecompounds of formula (D), as shown above in Reaction Scheme 1, where Ais ═C(H)—. Compounds of formula (D-1) can be prepared according to themethod disclosed below in Reaction Scheme 4:

Compounds of formula (Da) are commercially available or can be preparedby methods known to one skilled in the art or by methods disclosedherein.

In general, compounds of formula (D-1) are prepared, as set forth abovein Reaction Scheme 3, by first dissolving the compound of formula (Da)(1.0 equiv) in an anhydrous aprotic polar solvent or mixture of suchsolvents, for example, tetrahydrofuran with hexamethylphosphoramide(HMPA) (1.2 equiv). The resulting solution is stirred at ambienttemperature for about 10 minutes and then cooled to a temperature ofbetween about −10° C. and about 5° C., preferably at 0° C. A strongbase, lithium bis(trimethylsilyl)amide (Li-HMDS) (1.1 equiv), is thenadded dropwise to the stirred mixture over a period of time of betweenabout 20 minutes and 40 minutes, preferably over 30 minutes, whilemaintaining the temperature of the resulting mixture at between about−10° C. and about 5° C., preferably at 0° C. Ethyl bromoacetate (2.5equiv) is then added to the resulting anion of (Da) and the resultingmixture is stirred for additional period of time of between about 5minutes and 15 minutes, preferably for about about 10 minutes, and thenallowed to warm to ambient temperature and stirred at ambienttemperature for a period of time of between about 30 minutes and 3hours, preferably for about 2 hours. The compound of formula (Db) isthen isolated from the reaction mixture by standard isolation techniquesknown to one skilled in the art, such as solvent evaporation andpurification by flash column chromatography.

The compound of formula (Db) is then treated under basic hydrolysisconditions to form the compound of formula (Dc), which is isolated fromthe reaction mixture by standard isolation techniques known to oneskilled in the art.

The compound of formula (Dc) (1.0 equiv) is then treated with hydrazinehydrate (1.25 equiv) in the presence of a polar protic solvent, such asethanol, to yield the compound of formula (Dd), which is isolated fromthe reaction mixture by standard isolation techniques known to oneskilled in the art.

A mixture of the compound of formula (Dd) (1.0 equiv) and anhydrouscopper(II) chloride (2.0 equiv) is then refluxed in acetonitrile toyield the unsaturated compound of formula (De), which is isolated fromthe reaction mixture by standard isolation techniques known to oneskilled in the art.

A mixture of the compound of formula (De) and phosphoryl chloride, isrefluxed for a period of time of between about 1 hour and 3 hours,preferably for about 2 hours to aromatize and chlorinate the ringcontaining the N—N linkage. After cooling to ambient temperature, thecompound of formula (Df) is isolated from the reaction mixture bystandard isolation techniques known to one skilled in the art.

A mixture of the compound of formula (Df) (1.0 equiv) and anhydroushydrazine (19.8 equiv) in a protic solvent, such as ethanol, is refluxedfor a period time of between about 4 hours and 24 hours, preferably forabout 16 hours. After cooling to ambient temperature, water is added tothe mixture and the compound of formula (D-1) is then isolated from thereaction mixture by standard isolation techniques known to one skilledin the art.

All compounds of the invention which exist in free base or acid form canbe converted to their pharmaceutically acceptable salts by treatmentwith the appropriate inorganic or organic base or acid by methods knownto one of ordinary skill in the art. Salts of the compounds of theinvention can be converted to their free base or acid form by standardtechniques known to one skilled in the art.

The following specific Synthetic Preparations (for intermediates) andSynthetic Examples (for compounds of formula (Ia1) and (Ib1)) areprovided as a guide to assist in the practice of the invention, and arenot intended as a limitation on the scope of the invention.

Synthetic Preparation 1 Synthesis of7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene

A compound of formula (Ca)

A. Sodium methoxide (9.4 g, 174.2 mmol) was added to a 250 mL of flaskwith dry methanol (100 mL) at 0° C. After the solid was dissolved, theresulting solution was warmed to ambient temperature and was added to asolution of dimethyl acetone-1,3-dicarboxylate (15.2 g, 87.1 mmol) ando-xylylene dibromide, also known as 1,2-bis(bromomethyl)benzene, (20 g,75.7 mmol) in 100 mL of dry THF at 0° C. dropwise within 30 min. Afterthe addition, the reaction mixture was warmed to ambient temperature andstirred overnight. The volatiles were evaporated, the residue was pouredinto 40 mL of 10% HCl solution and extracted with ethyl acetate (EtOAc)(200 mL×2). The combined extracts were washed with water, saturatedNaHCO₃ solution and brine. After evaporation, the residual oil was usedfor next step directly.

B. The crude dimethyl7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6,8-dicarboxylate wasdissolved in 200 mL of ethanol (EtOH) and then 100 mL of 2 N KOH. Theresulting mixture was refluxed at 85° C. for 17 h. After cooling toambient temperature, the volatiles were evaporated. To the residue wasadded 120 mL of 2N HCl at 0° C., the crude product was extracted byEtOAc (200 mL×2). The combined extracts were washed with brine. Afterbeing dried (MgSO₄), filtered, and concentrated, the residue waspurified by flash column chromatography on silica gel (hexanes/EtOAc8:1) to afford 6.6 g (57%) of7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene as a white solid: mp 40-41°C.; ¹H NMR (300 MHz, CDCl₃) δ: 7.21 (m, 4H), 2.94-2.90 (m, 4H),2.63-2.60 (m, 4H); LC-MS: 161 (M+H)⁺.

Synthetic Preparation 2 Synthesis of2-nitro-8,9-dihydro-5H-benzo[7]annulene-7(6H)-one

A compound of formula (Cb)

To a solution of cold (0° C.) concentrated sulfuric acid (15 mL) wasadded 70% nitric acid (15 mL) dropwise over 30 min. The addition wascontrolled to maintain the internal reaction temperature below 5° C.After the addition, the resulting solution was transferred into anaddition funnel and was added dropwise to a solution of7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (14 g, 87.5 mmol) innitromethane (80 mL) at 0° C. over a period of 40 min. After theaddition, the reaction mixture was stirred at 0° C. for 2 h. Then icewater (˜80 mL) was added to the reaction mixture, and the mixture wasstirred for additional 30 min. Then the mixture was transferred to aseparatory funnel where the layers were separated. The aqueous layer wasextracted with ethyl acetate (3×80 mL). The combined layers were washedwith cold water, sat. NaHCO₃ solution and brine. After being dried(MgSO₄), filtered, and concentrated, the residue was purified by flashcolumn chromatography on silica gel (hexanes/EtOAc=3:1 to 2:1) to affordthe mixture of nitro regioisomers (˜15 g), which was then purified byrecrystallization from MTBE (tert-butyl methyl ether, 180 mL) to yield7.3 g of 2-nitro-8,9-dihydro-5H-benzo[7]annulene-7(6H)-one (40% yield)as a yellow solid: ¹H NMR (300 MHz, CDCl₃) δ: 8.10-8.06 (m, 2H),7.40-7.37 (m, 1H), 3.04-3.00 (m, 4H), 2.67-2.65 (m, 4H); LC-MS: 206(M+H)⁺.

Synthetic Preparation 3 Synthesis of1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine

A compound of formula (Cc)

Pyrrolidine (0.85 g, 12 mmol) and2-nitro-7-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene (2.05 g, 10 mmol)were mixed in 1,2-dichloroethane (35 mL) and then treated withNaBH(OAc)₃ (3.18 g, 15 mmol) and AcOH (0.60 g, 10 mmol). The mixture wasstirred at ambient temperature under a N₂ atmosphere overnight. Thereaction mixture was quenched with saturated NaHCO₃, and the product wasextracted with EtOAc (3×30 mL). The organic layers were combined anddried over NaSO₄. The solvent was evaporated and the residue waspurified by flash column chromatography eluting with CH₂Cl₂/DMA=1/1(DMA=CH₂Cl₂/MeOH/30% NH₃=80/19/1) to afford1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine, ayellow oil (2.2 g, 85%); MS (m/e): 261 (M+H⁺).

Synthetic Preparation 4 Synthesis of1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine

A compound of formula (Ba)

A mixture of1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine (2.0g; 7.69 mmol) and 10% palladium on carbon (0.2 g, ˜50% water) inmethanol (150 mL) was shaken under hydrogen (40 psi) for 1 h. After thistime the reaction mixture was filtered through diatomaceous earth andthe filtrate was concentrated under reduced pressure to afford1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine as anoil (quantitative yield); MS (m/e): 231 (M+H+).

Synthetic Preparation 5 Synthesis of PhenylN′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate

A compound of formula (C-1)

A mixture of1-(2-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-7-yl)pyrrolidine (1.7g; 7.39 mmol) and diphenyl cyanocarboimidate (1.76 g, 7.39 mmol) in 20mL of isopropanol was stirred at ambient temperature overnight. Thesolid was filtered, washed with isopropanol and ether and dried to givephenylN′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate,as a white solid (2.2 g, 80%). MS (m/e): 375 (M+H⁺).

Synthetic Preparation 6 Isolation of Phenyl(S)-N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidateand Phenyl(R)-N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidateEnantiomers of the Compound of Formula (C-1)

PhenylN′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate(0.43 g, racemic) was eluted on a chiral column chromatography mobilephase; ethanol/MeOH/triethyl amine=1/1/0.2% to afford phenyl(S)-N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidateand phenyl(R)-N′-cyano-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate:Chiral column: Chiralcel OJ, 21.2×250 mm. 10 μM; packing material:cellulose tris-(4-methylbenzoate) coated on 10 μm silica gel substrate.Flow rate 9.9 mL/min, sample solubility 30 mg/mL in methanol. Singleenantiomers were isolated in 170 mg and 190 mg quantities, respectively.Absolute configuration of each enantiomer was not determined at thistime.

Synthetic Preparation 7 Synthesis of ethyl2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetate Compound ofFormula (Db)

To a mixture of 1-benzosuberone (5.0 g, 31.2 mmol, Aldrich) in drytetrahydrofuran (THF) (20 mL) was added hexamethylphosphoramide (6.5 mL,37.5 mmol) (99%, Aldrich). The resulting mixture was stirred at ambienttemperature for 10 min and then cooled to 0° C. with a ice-water bath,1.0 M solution of lithium bis(trimethylsilyl)-amide in THF (32.7 mL,32.7 mmol) was added dropwise in 30 min. After the addition, thereaction mixture was stirred at 0° C. for 30 min. Ethyl bromoacetate(8.7 mL, 78.1 mmol) was then added. After stirring for a further 10 min,the reaction mixture was warmed to ambient temperature and stirred for 2h. Solvent was evaporated, the residue was diluted with ethyl acetate(EtOAc) (300 mL), and washed with water and brine. After being dried(MgSO₄), filtered, and concentrated, the residue was purified by flashcolumn chromatography eluting with hexanes-ethyl acetate 6:1-4:1) toafford 6.6 g of the compound of formula (Db), ethyl2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetate, as anorange oil (84%), ¹H NMR (300 MHz, CDCl₃) δ: 7.69-7.21 (m, 4H),4.22-4.05 (m, 2H), 3.40-3.30 (m, 1H), 3.12-2.92 (m, 3H), 2.52-2.43 (m,1H), 2.20-1.58 (m, 4H), 1.28-1.21 (m, 3H); LC-MS: purity: 91.8%; MS(m/e): 247 (MH⁺).

Synthetic Preparation 8 Synthesis of2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetic acidCompound of Formula (Dc)

The compound of formula (Db), ethyl2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetate, (6.6 g,26.8 mmol) was dissolved in ethanol (EtOH) (30 mL), then 10% potassiumhydroxide (KOH) aqueous solution (37.5 mL, 67 mmol) was added and theresulting mixture was refluxed for 2 h. After cooling to ambienttemperature, the EtOH was removed by evaporation. The residue wasextracted with EtOAc twice (15 mL×2). The aqueous layer was thentransferred into a flask and cooled with an ice-water bath, con. HCl wasadded dropwise to adjust pH to about 2.0. EtOAc (60 mL) was then added,the layers were separated, and the aqueous layer was extracted withEtOAc. The combined extracts were washed with brine. After being dried(MgSO₄), filtered, and concentrated, the compound of formula (Dc),2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetic acid, wasobtained as an orange oil (5.7 g, 97%); ¹H NMR (300 MHz, CDCl₃) δ:7.71-7.68 (m, 1H), 7.41-7.20 (m, 3H), 3.37-3.31 (m, 1H), 3.12-2.91 (m,3H), 2.57-2.49 (m, 1H), 2.15-1.90 (m, 2H), 1.75-1.62 (m, 2H); LC-MS:purity: 100%; MS (m/e): 219 (MH⁺).

Synthetic Preparation 9 Synthesis of4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-oneCompound of Formula (Dd)

A. A mixture of the compound of formula (Dc),2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-6-yl)acetic acid, (5.7g, 26.1 mmol) and hydrazine hydrate (1.6 mL, 32.7 mmol) in 20 mL ofethanol was refluxed for 2 h, cooled and filtered (washed with smallamount of EtOH) to give the compound of formula (Dd),4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one, as awhite solid (4.7 g, 84%); ¹H NMR (300 MHz, CDCl₃) δ: 8.61 (bs, 1H),7.53-7.14 (m, 4H), 2.98-2.75 (m, 3H), 2.58 (dd, J=15.3, 16.8 Hz, 1H),2.31 (dd, J=12.0, 16.8 Hz, 1H), 1.96-1.59 (m, 4H); LC-MS: purity: 100%;MS (m/e): 215 (MH⁺).

B. Alternatively, a mixture of benzosuberone (10.6 g, 66.2 mmol),glyoxylic acid monohydrate (6.08 g, 66.2 mmol), sodium hydroxide (10.6g, 265 mmol), ethanol (40 mL) and water (100 mL) were stirred overnightat ambient temperature, and then heated under reflux for 1 h. Themixture was cooled, then diluted with water and extracted twice withdichloromethane (subsequently discarded). The aqueous layer was thenacidified with 10% aqueous hydrochloric acid. Ice was added for cooling.The mixture was then filtered to give a pale yellow solid, 10.5 g (afterair drying). The crude solid was then heated at 100° C. for 1 h with amixture of acetic acid (60 mL), water (30 mL) and zinc dust (6 g). Thereaction mixture was cooled to ambient temperature and filtered. Thefiltrate was extracted with ethyl acetate. The organic layer was washedthree times with saturated sodium chloride solution, then dried overanhydrous sodium sulfate and concentrated under vacuum. The cruderesidue was heated with ethanol (25 mL) and hydrazine monohydrate (10mL) under reflux for 3 h. The solvent was removed under vacuum and theresidue was crystallized from benzene/ethanol, 1/1, to give4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one as awhite solid, 2.31 g; ¹H NMR (CDCl₃, 300 MHz) 8.66 (s, 1H), 7.52 (d, 1H),7.24-7.50 (m, 2H), 7.16 (d, 2H), 2.75-3.00 (m, 3H), 2.56 (dd, 1H), 2.31(dd, 1H), 1.60-1.90 (m, 4H) ppm; MS (ES) 215 (M+H). This procedurefollowed that reported by V. Peesapati and S. C. Venkata, Indian JChem., 41B, 839 (2002).

Synthetic Preparation 10 Synthesis of6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3 (5H)-one Compoundof Formula (De)

A. A mixture of the compound of formula (Dd),4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one (4.7g, 22 mmol) and anhydrous copper(II) chloride (6 g, 44 mmol) wasrefluxed in acetonitrile (45 mL) for 2 hours. After cooling to ambienttemperature, the mixture was poured into ice-water (200 g) and the solidobtained was washed with 10% HCl solution twice (about 20 mLx2) and coldwater twice (about 20 mLx2). After freeze-drying, the compound offormula (De),6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one (4.2 g,90%) was obtained as a white solid, ¹H NMR (300 MHz, CDCl₃) δ: 10.80(bs, 1H), 7.53-7.21 (m, 4H), 6.77 (s, 1H), 2.66 (t, J=6.9 Hz, 2H), 2.45(t, J=6.9 Hz, 2H), 2.14 (quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS(m/e): 213 (MH⁺).

B. Alternatively, a solution of4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[c]pyridazin-3(4H)-one (2.31g, 10.74 mmol), sodium m-nitrobenzenesulfonate (2.48 g, 11 mmol), sodiumhydroxide (1.86 g, 46.5 mmol) in water (80 mL) was heated under refluxfor 1.5 h. The solution was cooled to ambient temperature, and thenacidified with concentrated hydrochloric acid. The solid whichprecipitated was filtered off, washed with water and crystallized fromethanol to give6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one as tancrystals, 1.46 g; ¹H NMR (DMSO-d₆, 300 MHz) 13.04 (s, 1H), 7.25-7.45 (m,4H), 6.78 (s, 1H), 2.49 (m, 2H), 2.35 (m, 2H), 2.04 (m, 2H) ppm; MS (ES)213 (M+H).

Synthetic Preparation 11 Synthesis of3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine Compoundof Formula (Df)

A. A mixture of the compound of formula (De),6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one (4.0 g,19.3 mmol) and POCl₃ (20 mL) was refluxed for 2 h. After cooling toambient temperature, the volatiles were evaporated. The residue waspoured into a mixture of ice water and sodium bicarbonate, CH₂Cl₂ (200mL) was added to dissolve the solid. The layers were separated, and theaqueous layer was extracted with CH₂Cl₂ one more time. The combinedorganic layers were washed with brine. After being dried (MgSO₄),filtered, and concentrated, the compound of formula (Df),3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine wasobtained as a yellow solid (4.3 g, 99%), ¹H NMR (300 MHz, CDCl₃) δ: 7.82(m, 1H), 7.45-7.24 (m, 4H), 2.59-2.51 (m, 4H), 2.27 (quant, J=6.9 Hz,2H); LC-MS: purity: 100%; MS (m/e): 231 (MH⁺).

B. Alternatively, 6,7-dihydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(5H)-one was heated with 20 mL of phosphorus (III) oxychloride at 100°C. for 4.75 h. The solvent was removed under vacuum. The residue wastreated with ice and saturated sodium bicarbonate solution. The solidwhich formed was filtered off, washed well with water and air-dried toyield the corresponding3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6 g);¹H NMR (CDCl₃, 300 MHz) 7.82 (m, 1H), 7.44 (m, 2H), 7.39 (s, 1H), 7.27(m, 1H), 2.55 (m, 4H), 2.32 (m, 2H) ppm; MS (ES) 231/233 (M+H).

Synthetic Preparation 12 Synthesis of3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazineCompound of Formula (D-1)

A. A mixture of the compound of formula (Df),3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine, (4.3 g,18.6 mmol) and anhydrous hydrazine (11.7 mL, 370 mmol) in 45 mL ofethanol was refluxed for 16 h. After cooling to ambient temperature, 5mL of water was added and the volatiles were then evaporated. To thesolid residue was added cold water (about 80 mL). After sonication for10 min, the resulting solid was collected by filtration and washed withcold water three times. After freeze-drying, the compound of formula(D-1), 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine,(4.14 g, 98%) was obtained as a slight yellow solid, ¹H NMR (300 MHz,CD₃OD) δ: 7.59 (m, 1H), 7.39-7.26 (m, 3H), 7.04 (s, 1H), 2.54 (t, J=6.9Hz, 2H), 2.47 (t, J=6.9 Hz, 2H), 2.18 (quant, J=6.9 Hz, 2H); LC-MS:purity: 100%; MS (m/e): 227 (MH⁺).

B. Alternatively,3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.6 g)was heated with anhydrous hydrazine (4 mL) in ethanol (50 mL) at 100° C.for 4.75 h. The solvent was removed under vacuum. The residue waspartitioned between chloroform and 1M saturated aqueous potassiumcarbonate. The organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum to give3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine as abrown solid; ¹H NMR (CDCl₃, 300 MHz) 7.74 (m, 1H), 7.30 (m, 2H), 7.17(m, 1H), 6.92 (s, 1H), 2.49 (m, 2H), 2.39 (m, 2H), 2.12 (m, 2H) ppm; MS(ES) 227 (M+H).

Synthetic Preparation 13 Synthesis of PhenylN′-cyano-N-(7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate(Cb-5)

Finely ground 2-Nitro-8,9-dihydro-5H-benzo[7]annulen-7(6H)-one (8.00 g,39.0 mmol) and L-alanine (34.7 g, 390 mmol) were added to the reactionbuffer (1000 mL, Codexis/BioCatalytics). The mixture was stirredvigorously for about 20 min in order to obtain a uniform suspension(bright-yellow in color). The pyruvate reductase mix (40.0 g, PRM-102,Codexis/BioCatalytics) and the transaminase (0.85 g, ˜10.6 wt %,ATA-103) were added. The pH of the reaction mixture was ˜7. Stirring wascontinued at a slow pace; the pH was checked once a day and, ifnecessary, adjusted to pH 7.0-7.5 using 1M NaOH. During the course ofthe reaction the color of the mixture changed to a yellow-orange color.After 6 days HPLC analysis showed 99% conversion. The reaction wasworked up by adding sat. NaHCO₃ solution (200 mL) and CHCl₃ (600 mL).This mixture was stirred vigorously to ensure complete transfer of theproduct into the organic phase. After stirring overnight two layers hadformed and the organic layer contained large amounts of a gel-likesolid. The organic layer was separated and filtered through a largeglass frit (medium) to remove the gel-like solid. The aqueous phase wasextracted three times with DCM. The combined organic layers werefiltered through MgSO₄ and the solvents were evaporated to give thedesired amine, (7S)-2-nitro-7-amino-7,8,9-trihydro-5H-benzo[7]annulene(7.27 g, 91%, dark-red oil).

The single enantiomer was then BOC-protected, the nitro group reduced bytreatment with H₂/Pd and the primary aniline treated with diphenylcyanocarboimidate (slight excess) in 20 mL of isopropanol with stirringat ambient temperature overnight. The solid was filtered, washed withisopropanol and ether and dried to give phenyl(7S)-N′-cyano-N-(7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate,as a white solid in high yield (from the single enantiomer viatransamination).

Synthetic Example 1 Synthesis of1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine

PhenylN′-cyano-N-(7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)carbamimidate(2.00 g, 4.75 mmol) and3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1.08g, 4.75 mmol) were mixed in dry toluene (40 ml). The suspension washeated to 90° C. and stirred for 24 h. The clear solution was allowed tocool to ambient temperature and the toluene was evaporated using arotavapor. The crude product was then checked by HPLC and TLC. Columnchromatography on silica gel using CHCl₃ and 5% NH₃ (2M in MeOH)afforded some clean fractions of product which gave 367 mg (14%) of thedesired product,1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.The impure fractions were further purified by reverse phase HPLC toyield another 515 mg (20%) of the desired product, ¹H NMR (DMSO-d₆, 300MHz) 9.04 (s, 1H, NH), 7.92 (s, 1H), 7.86 (s, 2H), 7.69 (m, 1H), 7.43(m, 3H), 7.34 (m, 1H), 7.23 (m, 1H), 6.96 (d, 1H), 6.83 (d, 1H), 3.49(m, 1H), 2.72-2.39 (m, 8H), 2.22 (m, 2H), 2.07 (s, 1H), 1.92 (m, 2H),1.38 (s, 9H), 1.17 (m, 2H) ppm; trifluoroacetic acid salt MS (ES) 553.24(M+H), 551.42 (M−H).

Synthetic Example 2

The following compounds of the invention were prepared according to themethods similar to those described herein:

-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H-NMR (DMSO-d6, 300 MHz) 9.07 (s, 1H), 7.93 (s, 1H), 7.90-7.65 (m,    3H), 7.47-7.31 (m, 3H), 7.24 (s, 1H), 7.00 (d, 1H), 3.89-3.80 (m,    1H), 2.71-2.50 (m, 8H), 2.30-2.19 (m, 2H), 1.96-1.88 (m, 2H), 1.80    (s, 3H), 1.37-1.19 (m, 2H) ppm; MS (ES) 495.21 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H-NMR (CDCl₃, 300 MHz) 8.90-8.78 (m, 1H), 8.48 (bs, 2H), 7.93 (s,    1H), 7.80-7.78 (m, 1H), 7.47-7.41 (m, 2H), 7.38-7.30 (m, 3H),    7.05-7.00 (m, 1H), 3.82 (s, 3H), 3.80-3.64 (m, 2H), 2.94-2.81 (m,    3H), 2.79-2.71 (m, 4H), 2.70-2.67 (m, 3H), 2.38-2.43 (m, 4H),    2.38-2.29 (m, 3H), 1.80-1.60 (m, 2H) ppm; MS (ES) 565.29 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H-NMR (DMSO-d6, 300 MHz) 9.60 (s, 1H), 9.11 (s, 1H), 7.92 (s, 1H),    7.85 (s, 1H), 7.71-7.68 (m, 1H), 7.51-7.45 (m, 2H), 7.39-7.33 (m,    2H), 7.08 (d, 1H), 3.67 (t, 1H), 3.52 (d, 2H), 3.18 (bs, 2H),    2.84-2.52 (m, 6H), 2.37-2.22 (m, 8H), 1.58-1.41 (m, 3H) ppm; MS (ES)    557.23 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H-NMR (DMSO-d6, 300 MHz) 9.62 (s, 1H), 9.11 (s, 1H), 7.92 (s, 1H),    7.81 (s, 1H), 7.78-7.71 (m, 1H), 7.45-7.41 (m, 2H), 7.38-7.32 (m,    1H), 7.04 (d, 1H), 4.37 (d, 1H), 4.11 (d, 1H), 3.78 (s, 2H), 3.59    (t, 1H), 2.81-2.74 (m, 4H), 2.65-2.57 (m, 7H), 2.31-2.21 (m, 3H),    1.59-1.40 (m, 2H) ppm; MS (ES) 539.21 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H-NMR (DMSO-d6, 300 MHz) 9.55 (s, 1H), 9.18 (s, 1H), 7.94 (s, 1H),    7.72-7.68 (m, 1H), 7.47-7.40 (m, 2H), 7.38-7.31 (m, 2H), 7.05 (d,    1H), 5.05-4.70 (bs, 3H), 4.55 (q, 1H), 3.64 (t, 1H), 3.52-3.48 (m,    1H), 3.31-3.25 (m, 1H), 2.80-2.70 (m, 3H), 2.62-2.52 (m, 3H),    2.39-2.20 (m, 5H), 2.09-1.78 (m, 4H), 1.49-1.38 (m, 3H) ppm; MS (ES)    551.27 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H-NMR (DMSO-d6, 300 MHz) 9.11 (s, 1H), 8.97-8.90 (m, 1H), 7.94 (s,    1H), 7.85 (s, 1H), 7.71-7.68 (m, 1H), 7.50-7.40 (m, 2H), 7.38-7.30    (m, 2H), 7.05 (d, 1H), 4.09 (q, 2H), 3.55 (t, 1H), 3.38 (d, 1H),    3.10 (q, 1H), 2.85-2.57 (m, 5H), 2.52-2.42 (m, 6H), 2.29-2.18 (m,    3H), 2.06 (d, 2H), 1.77-1.70 (m, 2H), 1.54-1.36 (m, 3H), 1.29 (t,    3H) ppm; MS (ES) 593.28 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H-NMR (DMSO-d6, 300 MHz) 9.90 (bs, 1H), 9.10 (s, 1H), 7.96 (s, 2H),    7.74-7.69 (m, 1H), 7.50-7.41 (m, 2H), 7.37-7.40 (m, 1H), 7.05 (d,    1H), 4.40-3.83 (m, 5H), 3.53-3.44 (m, 1H), 3.36 (d, 1H), 3.12-2.98    (m, 1H), 2.83-2.71 (m, 2H), 2.62-2.59 (m, 1H), 2.57-2.43 (m, 7H),    2.41-2.36 (m, 1H), 2.29-2.20 (m, 1H), 2.02-1.91 (m, 2H), 1.50-1.38    (m, 1H) ppm; MS (ES) 565.26 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H-NMR (DMSO-d6, 300 MHz) 9.42 (s, 1H), 9.10 (s, 1H), 7.95 (s, 1H),    7.87 (s, 1H), 7.73-7.68 (m, 1H), 7.48-7.41 (m, 2H), 7.39-7.33 (m,    2H), 7.05 (d, 1H), 4.10 (bs, 3H), 3.57 (t, 1H), 2.78 (s, 3H),    2.68-2.45 (m, 9H), 2.34-2.22 (m, 3H). 1.55-1.39 (m, 2H) ppm; MS (ES)    525.22 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H-NMR (DMSO-d6, 300 MHz) 9.21 (s, 1H), 9.12 (s, 1H), 7.93 (s, 1H),    7.87 (s, 1H), 7.73-7.69 (m, 1H), 7.49-7.41 (m, 3H), 7.38-7.32 (m,    2H), 7.06 (d, 1H), 4.11 (q, 2H), 3.54-3.29 (m, 5H), 3.13-2.97 (m,    4H), 2.80-2.70 (m, 8H), 2.60 (t, 2H), 2.37-2.22 (m, 4H), 1.53-1.39    (m, 2H), 1.26 (t, 3H) ppm; MS (ES) 608.31 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 580.25 (M+H);    1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 507.24 (M+H), 505.33 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyccyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 507.25 (M+H), 505.28 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 553.31 (M+H), 551.47 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    formic acid salt ¹H NMR (DMSO-d₆, 300 MHz) 9.11 (s, 1H, NH), 7.93    (s, 1H), 7.65 (m, 3H), 7.72 (d, 1H), 7.47 (m, 2H), 7.38 (s, 1H),    7.27 (s, 1H), 7.03 (d, 1H), 3.32 (s, 1H), 2.71 (m, 4H), 2.65-2.45    (m, 4H), 2.21 (m, 4H), 1.29 (m, 2H) ppm; MS (ES) 553.65 (M+H),    551.37 (M−H); free base MS (ES) 453.65 (M+H), 451.39 (M−H);    trifluoroacetic acid salt MS (ES) 453.14 (M+H), 451.23 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7s)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.12 (s, 1H, NH), 7.95 (s, 1H), 7.82 (s,    2H, NH₂), 7.71 (m, 1H), 7.45 (m, 3H), 7.31 (m, 2H), 7.05 (d, 2H),    3.75 (t, 1H), 2.96 (m, 4H), 2.73 (m, 4H), 2.65-2.42 (m, 4H), 2.23    (m, 4H), 1.31 (m, 2H), 1.08 (s br, 2H), 0.61 (d, 4H), 0.29 (d, 4H)    ppm; MS (ES) 561.30 (M+H), 559.42 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.13 (s, 1H), 8.25 (s br, 2H), 7.81-8.00    (m, 3H), 7.66-7.76 (m, 1H), 7.41-7.53 (m, 3H), 7.27-7.39 (m, 2H),    6.97-7.11 (m, 1H), 3.19-3.47 (m, 1H), 2.66-2.86 (m, 6H), 2.43-2.65    (m, 7H), 2.14-2.37 (m, 4H), 1.82-1.99 (m, 1H), 1.20-1.47 (m, 2H),    0.93 (d, J=6.6 Hz, 6H) ppm; MS (ES) 509.23 (M+H), 507.36 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.06-9.18 (m, 1H), 8.19-8.40 (m, 2H),    7.76-7.99 (m, 3H), 7.23-7.54 (m, 5H), 7.03 (d, 1H), 3.20-3.44 (m,    1H), 2.83-3.00 (m, 2H), 2.66-2.82 (m, 4H), 2.51-2.66 (m, 4H),    2.11-2.34 (m, 4H), 1.46-1.73 (m, 2H), 1.19-1.44 (m, 2H), 0.91 (s,    3H) ppm; MS (ES) 495.24 (M+H), 493.38 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.12 (s, 1H), 8.67-8.85 (m, 1H),    7.77-8.02 (m, 3H), 7.65-7.76 (m, 1H), 7.25-7.56 (m, 5H), 7.05 (d,    J=8.3 Hz, 1H), 3.47-3.70 (m, 1H), 2.99-3.18 (m, 2H), 2.83-2.98 (m,    2H), 2.66-2.83 (m, 4H), 2.50-2.66 (m, 5H), 2.10-2.34 (m, 4H),    1.34-1.78 (m, 6H), 0.88 (t, J=7.2 Hz, 5H) ppm; MS (ES) 537.30 (M+H),    535.49 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.10 (s, 1H), 7.94 (s, 1H), 7.83 (s br,    2H), 7.67-7.75 (m, 1H), 7.41-7.53 (m, 3H), 7.29-7.41 (m, 2H), 7.05    (d, 1H), 3.52-3.68 (m, 2H), 2.93-3.27 (m, 4H), 2.66-2.85 (m, 4H),    2.50-2.65 (m, 4H), 2.11-2.31 (m, 5H), 1.33-1.60 (m, 2H), 1.09-1.29    (m, 7H) ppm; MS (ES) 509.23 (M+H), 507.35 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 535.30 (M+H), 533.46 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 521.28 (M+H), 519.28 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 563.30 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.09 (s, 1H), 8.32 (s, 1H), 7.94 (s, 1H),    7.84 (s, 2H), 7.63-7.77 (m, 1H), 7.40-7.52 (m, 2H), 7.36 (s br, 1H),    7.28 (s, 1H), 7.01 (d, 1H), 3.16-3.35 (m, 2H), 3.10-3.16 (m, 1H),    2.65-2.80 (m, 4H), 2.56-2.65 (m, 2H), 2.07-2.33 (m, 5H), 1.19-1.40    (m, 2H), 1.16 (d, J=6.3 Hz, 6H) ppm; MS (ES) 495.26 (M+H), 493.37    (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 536.18 (M);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 549.28 (M+H), 547.29 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 645.43 (M+H), 643.51 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((5-chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.12 (s, 1H), 8.86 (s br, 2H), 7.66-7.99    (m, 3H), 7.26-7.53 (m, 4H), 7.17 (d, 2H), 7.04 (d, 1H), 4.43 (s br,    2H), 3.21-3.36 (m, 2H), 2.65-2.86 (m, 7H), 2.13-2.39 (m, 4H),    1.17-1.50 (m, 2H) ppm; MS (ES) 583.15 (M+H), 581.28 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 587.26 (M+H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.09 (s, 1H), 8.01 (s, 1H), 7.67-7.96 (m,    6H), 7.27-7.50 (m, 5H), 7.03 (d, 1H), 6.50 (s, 1H), 4.12 (s br, 1H),    3.05-3.20 (m, 3H), 2.65-2.79 (m, 4H), 2.55-2.64 (m, 2H), 2.15-2.37    (m, 4H), 1.17-1.46 (m, 3H) ppm; MS (ES) 623.00 (M+H), 619.06 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.06 (s, 1H), 8.25 (s br, 2H), 7.81-8.01    (m, 3H), 7.65-7.78 (m, 2H), 7.25-7.51 (m, 2H), 6.97-7.08 (m, 1H),    4.86-5.00 (m, 1H), 3.99-4.08 (m, 1H), 2.66-2.85 (m, 2H), 2.52-2.65    (m, 4H), 2.15-2.36 (m, 5H), 1.87-2.12 (m, 5H), 1.12-1.48 (m, 3H)    ppm; MS (ES) 481.10 (M+H), 479.13 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 507.15 (M+H), 505.24 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 523.16 (M+H), 521.27 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.05 (s, 1H), 8.29 (s, 1H), 7.93 (s, 1H),    7.85 (s br, 2H), 7.61-7.75 (m, 1H), 7.32-7.49 (m, 3H), 7.28 (s, 1H),    6.99 (d, 1H), 2.82-2.96 (m, 1H), 2.65-2.78 (m, 3H), 2.56-2.65 (m,    2H), 2.36-2.54 (m, 5H), 2.17-2.33 (m, 2H), 1.99-2.16 (m, 2H),    1.15-1.42 (m, 2H), 0.88 (s, 9H) ppm; MS (ES) 523.16 (M+H), 521.26    (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 617.28 (M+H), 615.31 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.07 (s, 1H), 8.34 (s, 1H), 7.94 (s, 1H),    7.84 (s br, 2H), 7.66-7.75 (m, 1H), 7.33-7.53 (m, 3H), 7.28 (s, 1H),    7.00 (d, 1H), 2.87-3.13 (m, 1H), 2.40-2.84 (m, 10H), 1.92-2.33 (m,    5H), 1.63-1.80 (m, 2H), 1.39-1.63 (m, 4H), 1.05-1.38 (m, 4H) ppm; MS    (ES) 535.18 (M+H), 533.16 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 665.26 (M+H), 663.40 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.03 (s, 1H), 8.32 (s, 1H), 7.92 (s, 1H),    7.83 (s br, 2H), 7.63-7.75 (m, 1H), 7.32-7.55 (m, 3H), 7.27 (s, 1H),    6.99 (d, 1H), 6.08-6.21 (m, 1H), 5.89-6.01 (m, 1H), 2.83-3.03 (m,    2H), 2.65-2.82 (m, 4H), 2.54-2.65 (m, 4H), 2.29-2.44 (m, 4H),    1.93-2.33 (m, 6H), 1.81 (t, 1H), 1.14-1.37 (m, 4H), 0.39-0.60 (m,    1H) ppm; MS (ES) 559.17 (M+H), 557.39 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.08 (s, 1H), 8.34 (s, 1H), 7.93 (s, 1H),    7.86 (s br, 2H), 7.67-7.74 (m, 1H), 7.40-7.51 (m, 3H), 7.33-7.39 (m,    1H), 7.29 (s br, 1H), 7.01 (d, J=8.3 Hz, 1H), 3.08 (s br, 1H),    2.52-2.87 (m, 10H), 2.07-2.33 (m, 4H), 1.52-1.68 (m, 1H), 1.35-1.48    (m, 2H), 1.17-1.34 (m, 2H), 0.87 (d, J=6.3 Hz, 6H) ppm; MS (ES)    523.20 (M+H), 521.27 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.01 (s, 1H), 7.91 (s, 1H), 7.83 (s br,    2H), 7.67-7.74 (m, 1H), 7.39-7.49 (m, 3H), 7.33-7.39 (m, 1H),    7.25-7.31 (m, 1H), 6.99 (d, J=8.3 Hz, 1H), 2.52-2.75 (m, 9H),    2.16-2.38 (m, 7H), 1.86-2.04 (m, 2H), 1.49-1.62 (m, 2H), 1.11-1.28    (m, 5H), 0.83 (d, J=6.6 Hz, 12H) ppm; MS (ES) 593.28 (M+H), 591.33    (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): ¹H NMR (DMSO-d₆) δ: 9.04 (s, 1H), 8.28    (s, 1H), 7.93 (s, 1H), 7.84 (s br, 2H), 7.66-7.75 (m, 1H), 7.40-7.50    (m, 3H), 7.32-7.40 (m, 1H), 7.29 (s, 1H), 7.01 (d, J=8.3 Hz, 1H),    2.96-3.11 (m, 1H), 2.44-2.82 (m, 13H), 2.06-2.30 (m, 4H), 1.17-1.51    (m, 6H), 0.82 (t, J=7.3 Hz, 6H) ppm; MS (ES) 537.20 (M+H), 535.27    (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 507.16 (M+H), 505.11 (M−H);-   1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 562.16 (M);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    MS (ES) 554.10 (M+H), 552.22 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz): 9.23 (s, 1H), 8.54-8.69 (m, 1H), 8.10 (d,    1H), 7.98 (s, 1H), 7.87 (s br, 2H), 7.31-7.56 (m, 3H), 6.97 (t, 1H),    3.38-3.43 (m, 3H), 2.53-2.80 (m, 6H), 2.18-2.41 (m, 5H), 1.97-2.15    (m, 2H), 1.84-1.97 (m, 3H), 1.42-1.76 (m, 4H) ppm; MS (ES) 541.63    (M+H), 539.45 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.04 (s, 1H), 8.59 (d, 1H), 8.21 (s, 1H),    8.06 (d, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.62-7.43 (m, 2H), 7.26    (s, 1H), 6.95 (d, 1H) 2.92 (m, 1H), 2.68-2.42 (m, 4H), 2.44 (s, 2H),    2.29 (m, 2H), 2.05 (m, 2H), 1.29 (m, 2H), 1.01 (m, 4H) ppm; MS (ES)    454.37 (M+H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.03 (s, 1H), 8.53 (d, 1H), 8.25 (s, 1H),    8.11 (d, 1H), 7.95 (s, 1H), 7.88 (s, 1H), 7.51-7.39 (m, 2H), 7.26    (s, 1H), 7.08 (d, 1H), 2.92 (m, 1H), 2.72-2.48 (m, 8H), 2.40 (s,    2H), 2.31 (m, 2H), 2.02 (m, 2H), 1.25 (m, 2H), 1.06 (m, 4H) ppm; MS    (ES) 482.08 (M+H), 480.23 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.05 (s, 1H), 8.58 (d, 1H), 8.22 (s, 1H),    8.09 (d, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.56-7.38 (m, 2H), 7.28    (s, 1H), 7.03 (d, 1H), 2.98 (m, 1H), 2.79-2.52 (m, 12H), 2.49 (s,    2H), 2.33 (m, 2H), 2.04 (m, 2H), 1.27 (m, 2H), 1.03 (m, 4H) ppm; MS    (ES) 510.57 (M+H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.04 (s, 1H), 8.58 (d, 1H), 8.18 (s, 1H),    8.08 (d, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.60-7.40 (m, 2H), 7.28    (s, 1H), 6.99 (d, 1H), 2.86-2.56 (m, 10H), 2.41-2.24 (m, 6H), 1.99    (m, 2H), 1.50-1.09 (m, 5H), 0.82 (t, 6H) ppm; MS (ES) 538.15 (M+H),    536.25 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.05 (s, 1H), 8.60 (d, 1H), 8.21 (s, 1H),    8.09 (d, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.55-7.39 (m, 2H), 7.26    (s, 1H), 7.00 (d, 1H), 3.10 (t, 2H), 2.77-2.54 (m, 8H), 2.45-2.22    (m, 6H), 2.01 (m, 4H), 1.30-1.09 (m, 2H), 0.84 (m, 2H), 0.43 (d,    3H), 0.10 (d, 2H) ppm; MS (ES) 562.16 (M+H), 560.39 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.04 (s, 1H), 8.59 (d, 1H), 8.21 (s, 1H),    8.06 (d, 1H), 7.99 (s, 1H), 7.84 (s, 1H), 7.62-7.43 (m, 2H), 7.26    (s, 1H), 6.95 (d, 1H), 2.83-2.59 (m, 6H), 2.51-2.31 (m, 6H), 2.01    (m, 2H), 1.66-1.38 (m, 5H), 1.24 (m, 6H), 0.88 (d, 6H), 0.83 (d, 6H)    ppm; MS (ES) 594.21 (M+H); 592.25 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.04 (s, 1H), 8.59 (d, 1H), 8.29 (s, 1H),    8.10 (d, 1H), 7.96 (s, 1H), 7.85 (s, 1H), 7.55-7.39 (m, 2H), 7.24    (s, 1H), 6.99 (d, 1H), 2.93-2.53 (m, 8H), 2.31 (m, 4H), 2.11 (m,    2H), 1.96 (m, 2H), 1.80 (m, 2H), 1.62 (m, 2H), 1.32-1.10 (m, 2H)    ppm; MS (ES) 508.05 (M+H), 506.13 (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.06 (s, 1H), 8.60 (d, 1H), 8.31 (s, 1H),    8.10 (d, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.54-7.39 (m, 2H), 7.27    (s, 1H), 6.97 (d, 1H), 2.89-2.58 (m, 8H), 2.52 (m, 2H), 2.36 (m,    2H), 2.09 (m, 2H), 1.87 (m, 2H), 1.70 (m, 2H), 1.56 (m, 2H),    1.36-1.01 (m, 6H) ppm; MS (ES) 536.12 (M+H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.04 (s, 1H), 8.57 (d, 1H), 8.32 (s, 1H),    8.09 (d, 1H), 7.94 (s, 1H), 7.84 (s, 1H), 7.57-7.38 (m, 2H), 7.22    (s, 1H), 6.96 (d, 1H), 3.18-3.32 (m, 2H), 3.16-3.12 (m, 1H),    2.80-2.64 (m, 4H), 2.66-2.56 (m, 2H), 2.35-2.07 (m, 5H), 1.41-1.08    (m, 2H), 1.15 (d, J=6.3 Hz, 6H) ppm; MS (ES) 496.09 (M+H), 494.12    (M−H);-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.05 (s, 1H), 8.61 (d, 1H), 8.21 (s, 1H),    8.11 (d, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.57-7.39 (m, 2H), 7.29    (s, 1H), 6.96 (d, 1H), 3.36 (m, 2H) 2.81-2.52 (m, 8H), 2.45-2.21 (m,    6H), 2.01 (m, 2H), 1.87-1.44 (m, 4H), 1.29 (m, 2H) ppm; MS (ES)    522.12 (M+H), 520.31 (M−H); and-   1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,    ¹H NMR (DMSO-d₆, 300 MHz) 9.06 (s, 1H), 8.60 (d, 1H), 8.27 (s, 1H),    8.07 (d, 1H), 7.98 (s, 1H), 7.87 (s, 1H), 7.59-7.43 (m, 2H), 7.20    (s, 1H), 7.01 (d, 1H), 3.28 (m, 2H), 2.95-2.63 (m, 8H), 2.19 (m,    5H), 1.75 (m, 2H), 1.41-1.11 (m, 2H), 0.95 (t, 3H) ppm; MS (ES)    510.09 (M+H), 508.38 (M−H).

BIOLOGICAL EXAMPLES

The following biological examples are provided by way of illustration,not limitation. In the following biological examples,1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine,which is a compound of formula (I), as set forth above in the Summary ofthe Invention, and which is designated in the following examples andFIGS. 1-8 as “Compound A” or “Cpd A” or “Cmpd A”, was assayed for itsability to prevent, treat or manage metastatic cancer, either alone orin combination with another chemotherapeutic agent.

Biological Example 1 Efficacy of Compound A in Preventing Lung and LiverMetastasis of a Primary Tumor in Breast Tissue

Using a variation of the mouse 4T1 breast tumor model, as described inCurrent Protocols in Immunology (2000), 20.2.1-20.2.16, Compound A wasassayed to determine its ability to prevent, treat or manage metastaticcancer in BALB/c mice.

Formulations

-   Vehicle: 0.5% HPMC/0.1% Tween.-   Compound A: Preformulated dosing solutions in vehicle for 25 mg/kg,    40 mg/kg and 75 mg/kg for oral administration.-   Cisplatin (Reference Control): Diluted in sterile saline for 1.2    mg/kg, 2.4 mg/kg and 75 mg/kg for intravenous administration.-   Zometa: Diluted in sterile saline as per clinical formulation for    subcutaneous administration.

Protocol

Eighty-eight BALB/c mice were inoculated with 5×10⁵ 4T1 tumor cells(ATCC) orthotoically into the third mammary fat pad. On Day 0 of thestudy (2 days post-inoculation), 80 mice were randomized into 8 groups(10 mice per group). Dose administration began on Day 0 and continuedfor 21 days (3 weeks). Compound A was administered twice a day,Cisplatin was administered once a week, and Zometa was administeredthree times weekly. Tumor measurements were performed three times perweek, starting when tumors were palpable (approximately 3×3 mm). Bodyweight measurements were taken three times per week at the same timeeach day. Tumor and body weight measurements fall all mice were measuredprior to dose administration.

On Day 21 of the treatment, mice were euthanized and the lungs exposedand the numbers of surface lung metastases were counted. The size ofeach metastasis was measured using a caliper in one dimension andcategorized as follows:

Small: Less than 2 mm

Medium: Greater or equal to 2 mm

Large: Greater or equal to 3 mm

The lungs and livers from all mice were excised and placed in PLPfixative and stained for micrometastasis quantification.

Results

The results of this assay with respect to the effect of Compound A onthe total number of macroscopic lung metastases are shown in FIG. 1.

The results of this assay with respect to the effect of Compound A onthe number of medium lung metastases are shown in FIG. 2. The differencebetween the effect of Compound A at 45 mg/kg and the vehicle wassignificant (p<0.05, Mann-Whitney Test). The difference between theeffect of cisplatin at 4 mg/kg and the vehicle was significant (p<0.001,Mann-Whitney Test).

The results of this assay with respect to the effect of Compound A onthe number of large lung metastases are shown in FIG. 3. The differencebetween the effect of Compound A at 25 mg/kg and the vehicle wassignificant (p<0.05, Mann-Whitney Test). The difference between theeffect of Cisplatin at 1.2 mg/kg and 2.4 mg/kg and the vehicle wassignificant (p<0.05, Mann-Whitney Test).

The results of this assay with respect to the effect of Compound A onthe incidence of liver micrometastases are shown in FIG. 4. Thedifference between the effect of Compound A at 25 mg/kg, 45 mg/kg and 75mg/kg and the vehicle was significant (p<0.05, Mann-Whitney Test). Thedifference between the effect of Cisplatin at 2.4 mg/kg and 4 mg/kg andthe effect of Cisplatin at 1.2 mg/kg was significant (p<0.05,Mann-Whitney Test). The difference between the effect of Compound A at45 mg/kg and 75 mg/kg and the effect of Compound A at 25 mg/kg wassignificant (p<0.05, Mann-Whitney Test). The difference between theeffect of Zometa at 0.1 mg/kg and the vehicle was significant (p<0.05,Mann-Whitney Test).

Biological Example 2 Efficacy of Compound A in Combination withCisplatin in Preventing Lung and Liver Metastasis of a Primary Tumor inBreast Tissue

Using a variation of the mouse 4T1 breast tumor model, as described inCurrent Protocols in Immunology (2000), 20.2.1-20.2.16, Compound A incombination with Cisplatin was assayed to determine the efficacy of thecombination therapy to prevent, treat or manage metastatic cancer inBALB/c mice.

Formulations

-   Vehicle: 0.5% HPMC/0.1% Tween.-   Compound A: Preformulated dosing solutions in vehicle for 7 mg/kg    and 21 mg/kg for oral administration.-   Cisplatin: Diluted in sterile saline for 1.2 mg/kg (suboptimal    clinical formulation) for intravenous administration.

Protocol

Sixty-six BALB/c mice were inoculated with 5×10⁵ 4T1 tumor cells (ATCC)orthotoically into the third mammary fat pad. On Day 0 of the study (2days post-inoculation), 60 mice were randomized into 6 groups (10 miceper group). Dose administration began on Day 0 and continued for 21 days(3 weeks). Compound A was administered twice a day, Cisplatin wasadministered once a week, and Zometa was administered three timesweekly. Tumor measurements were performed three times per week, startingwhen tumors were palpable (approximately 3×3 mm). Body weightmeasurements were taken three times per week at the same time each day.Tumor and body weight measurements fall all mice were measured prior todose administration.

On Day 21 of the treatment, mice were euthanized and the lungs exposedand the number of surface lung metastases were counted. The size of eachmetastasis was measured using a caliper in one dimension and categorizedas follows:

Small: Less than 2 mm

Medium: Greater or equal to 2 mm

Large: Greater or equal to 3 mm

The lungs and livers from all mice were excised and placed in PLPfixative and stained for micrometastasis quantification.

Results

The results of this assay with respect to the effect of the combinationtherapy of Compound A and Cisplatin on the size of the primary tumor isshown in FIG. 5.

The results of this assay with respect to the effect of the combinationtherapy of Compound A and Cisplatin on the incidence of livermicrometastases is shown in FIG. 6. The difference between the effect ofboth combination therapies (Compound A at 7 mg/kg or 21 mg/kg andCisplatin at 1.2 mg/kg) and the effect of the vehicle alone or theactive ingredients (Cisplatin or Compound A) alone was significant(p<0.05, Mann-Whitney Test).

The results of this assay with respect to the effect of the combinationtherapy of Compound A and Cisplatin on reducing the number of large lungmetastases is shown in FIG. 7. The difference between the effect ofCompound A at 21 mg/kg and 7 mg/kg and vehicle was significant (p<0.01,Mann-Whitney Test). The difference between the effect of Cisplatin at1.2 mg/kg and vehicle was significant (p<0.05, Mann-Whitney Test).

The results of this assay with respect to the effect of the combinationtherapy of Compound A and Cisplatin on reducing the incidence of largelung metastases is shown in FIG. 8. The difference between the effect ofboth combination therapies (Compound A at 7 mg/kg or 21 mg/kg andCisplatin at 1.2 mg/kg) and the effect of the vehicle alone wassignificant (p<0.05, Mann-Whitney Test).

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

What is claimed is:
 1. A method for treating or managing cancer in apatient in need thereof, wherein the method comprises administering tothe patient a therapeutically effective amount of an Axl inhibitor and atherapeutically effective amount of one or more chemotherapeutic agents,wherein the Axl inhibitor is a compound of formula (I):

wherein: R¹, R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, —C(O)R⁸,—C(O)N(R⁶)R⁷, and —C(═NR⁶)N(R⁶)R⁷; R² and R³ are each independently apolycyclic heteroaryl containing more than 14 ring atoms optionallysubstituted by one or more substituents selected from the groupconsisting of oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl,optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heteroaryl, optionally substitutedheterocyclyl, —R⁹—OR⁸, —R⁹—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—O—R¹⁰—OR⁸, —R⁹—O—R¹⁰—CN,—R⁹—O—R—C(O)OR⁸, —R⁹—O—R¹⁰—C(O)N(R⁶)R⁷, —R⁹—O—R—S(O)_(p)R⁸ (where p is0, 1 or 2), —R⁹—O—R¹⁰—N(R⁶)R⁷, —R⁹—O—R¹⁰—C(NR¹¹)N(R¹¹)H, —R⁹—OC(O)—R⁸,—R⁹—N(R⁶)R⁷, —R⁹—C(O)R⁸, —R⁹—C(O)OR⁸, —R⁹—C(O)N(R⁶)R⁷, —R⁹—N(R⁶)C(O)OR⁸,—R⁹—N(R⁶)C(O)R⁸, —R⁹—N(R⁶)S(O)_(t)R⁸ (where t is 1 or 2),—R⁹—S(O)_(t)OR⁸ (where t is 1 or 2), —R⁹—S(O)_(p)R⁸ (where p is 0, 1 or2), and —R⁹—S(O)_(t)N(R⁶)R⁷ (where t is 1 or 2); or R² is a polycyclicheteroaryl containing more than 14 ring atoms as described above and R³is selected from the group consisting of aryl and heteroaryl, where thearyl and the heteroaryl are each independently optionally substituted byone or more substitutents selected from the group consisting of alkyl,alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo,thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl,optionally substituted cycloalkylalkynyl, optionally substitutedheterocyclyl, optionally substituted heterocyclylalkyl, optionallysubstituted heterocyclylalkenyl, optionally substitutedheterocyclylalkynyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted heteroarylalkenyl,optionally substituted heteroarylalkynyl, —R¹³—OR¹², —R¹³—OC(O)—R¹²,—R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂,—R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹², —R¹³—C(O)N(R¹²)₂,—R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³, —R¹³—C(O)N(R¹²)—R¹⁴—OR¹²,—R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹², —R¹³—N(R¹²)S(O)_(t)R¹² (where tis 1 or 2), —R¹³—S(O)_(t)OR¹² (where t is 1 or 2), —R¹³—S(O)_(p)R¹²(where p is 0, 1 or 2), and —R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2); orR³ is a polycyclic heteroaryl containing more than 14 ring atoms asdescribed above, and R² is selected from the group consisting of aryland heteroaryl, where the aryl and the heteroaryl are each independentlyoptionally substituted by one or more substitutents selected from thegroup consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl,haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, optionally substituted heteroarylalkynyl,—R¹³—OR¹², —R¹³—OC(O)—R¹², —R¹³—O—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)—R¹⁴—N(R¹²)₂,—R¹³—N(R¹²)—R¹⁴—N(R¹²)₂, —R¹³—N(R¹²)₂, —R¹³—C(O)R¹², —R¹³—C(O)OR¹²,—R¹³—C(O)N(R¹²)₂, —R¹³—C(O)N(R¹²)—R¹⁴—N(R¹²)R¹³,—R¹³—C(O)N(R¹²)—R¹⁴—OR¹², —R¹³—N(R¹²)C(O)OR¹², —R¹³—N(R¹²)C(O)R¹²,—R¹³—N(R¹²)S(O)_(t)R¹² (where t is 1 or 2), —R¹³—S(O)_(t)OR¹² (where tis 1 or 2), —R¹³—S(O)_(p)R¹² (where p is 0, 1 or 2), and—R¹³—S(O)_(t)N(R¹²)₂ (where t is 1 or 2); each R⁶ and R⁷ isindependently selected from the group consisting of hydrogen, alkyl,alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted cycloalkylalkenyl, optionally substitutedcycloalkylalkynyl, optionally substituted heterocyclyl, optionallysubstituted heterocyclylalkyl, optionally substitutedheterocyclylalkenyl, optionally substituted heterocyclylalkynyl,optionally substituted heteroaryl, optionally substitutedheteroarylalkyl, optionally substituted heteroarylalkenyl, optionallysubstituted heteroarylalkynyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R¹⁰—NO₂, —R¹⁰—N(R⁸)₂,—R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or any R⁶ and R⁷, together with thecommon nitrogen to which they are both attached, form an optionallysubstituted N-heteroaryl or an optionally substituted N-heterocyclyl;each R⁸ is independently selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heterocyclylalkenyl,optionally substituted heterocyclylalkynyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, optionallysubstituted heteroarylalkenyl, and optionally substitutedheteroarylalkynyl; each R⁹ is independently selected from the groupconsisting of a direct bond, an optionally substituted straight orbranched alkylene chain, an optionally substituted straight or branchedalkenylene chain and an optionally substituted straight or branchedalkynylene chain; each R¹⁰ is independently selected from the groupconsisting of an optionally substituted straight or branched alkylenechain, an optionally substituted straight or branched alkenylene chainand an optionally substituted straight or branched alkynylene chain;each R¹¹ is independently selected from the group consisting ofhydrogen, alkyl, cyano, nitro and —OR⁸; each R¹² is independentlyselected from the group consisting of hydrogen, alkyl, alkenyl,haloalkyl, optionally substituted cycloalkyl, optionally substitutedcycloalkylalkyl, optionally substituted aryl, optionally substitutedaralkyl, optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, —R¹⁰—OR⁸, —R¹⁰—CN, —R⁰—NO₂, —R¹⁰—N(R⁸)₂,—R¹⁰—C(O)OR⁸ and —R¹⁰—C(O)N(R⁸)₂, or two R^(12's), together with thecommon nitrogen to which they are both attached, form an optionallysubstituted N-heterocyclyl or an optionally substituted N-heteroaryl;each R¹³ is independently selected from the group consisting of a directbond, an optionally substituted straight or branched alkylene chain andan optionally substituted straight or branched alkenylene chain; andeach R¹⁴ is independently selected from the group consisting of anoptionally substituted straight or branched alkylene chain and anoptionally substituted straight or branched alkenylene chain; or astereoisomer, tautomer, pharmaceutically acceptable salt or N-oxidethereof.
 2. The method of claim 1 wherein the compound of formula (I) isselected from the group consisting of:1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(3-fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-(7-(S)-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(methoxycarbonyl)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4,4-difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((2R)-2-(carboxy)pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-((carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(4-(carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-1-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7s)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((1-cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3,3-dimethylbut-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((5-chiorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2-carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((3-bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((2,2-dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N⁵-((7S)-7-(t-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-((methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine;and1-(6,7-dihydro-5H-pyrido[2′,3′:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N³-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-yl)-1H-1,2,4-triazole-3,5-diamine.3. The method of claim 1 wherein the one or more chemotherapeutic agentsis selected from the group consisting of antimetabolites, alkylatingagents, coordination compounds, platinum complexes, DNA cross-linkingcompounds, inhibitors of transcription enzymes, tyrosine kinaseinhibitors, protein kinase inhibitors, topoisomerase inhibitors, DNAminor-groove binding compounds, vinca alkyloids, taxanes, antitumorantibiotics, hormones, aromatase inhibitors, enzymes, growth factorreceptors antibodies, cytokines, cell surface markers antibodies, HDACinhibitors, HSP 90 inhibitors, BCL-2 inhibitors, mTOR inhibitors,proteasome inhibitors and monoclonal antibodies.
 4. The method of claim3 wherein the one or more chemotherapeutic agents is selected from thegroup consisting of mechlorothamine, cyclophosphamide, ifosfamide,melphalan, chlorambucil, ethyleneimines, methylmelamines, procarbazine,dacarbazine, temozolomide, busulfan, carmustine, lomustine,methotrexate, fluorouracil, capecitabine, cytarabine, gemcitabine,cytosine arabinoside, mecaptopurine, fludarabine, cladribine,thioguanine, azathioprine, vinblastine, vincristine, paclitaxel,docetaxel, colchicine, actinomycin D, daunorubicin, bleomycin,L-asparaginase, cisplatin, carboplatin, oxaliplatin, prednisone,dexamethasone, amino glutethimide, formestane, anastrozole,hydroxyprogesterone caproate, medroxyprogesterone, tamoxifen, amsacrine,mitoxantrone, topotecan, irinotecan, camptothecin, axtinib, bosutinib,cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib,lestaurtinib, nilotinib, semaxanib, sunitinib, vandetanib, vatalanib,anti-Her2 antibodies, interferon-α, interferon-γ, interleukin-2, GM-CSF,anti-CTLA-4 antibodies, rituximab, anti-CD33 antibodies, MGCD0103,vorinostat, 17-AAG, thalidomide, lenalidomide, rapamycin, CCI-779,sorafenib, doxorubicine, gemcitabine, melphalan, bortezomib, NPI052,gemtuzumab, alemtuzumab, ibritumomab tiuxaetan, tositumomab, iodine-131tositumomab, trastuzumab, bevacizumab, rituximab, and anti-TRAIL deathreceptor antibodies.